2024-03-28T12:49:40Zhttp://repository.helmholtz-hzi.de/oai/requestoai:repository.helmholtz-hzi.de:10033/1281132019-08-30T11:36:32Zcom_10033_128109col_10033_128110
Toker, Aras
951e6c8c112099fb39179e3cf1ea0d14
500
Huehn, Jochen
81855dd40035a02edad8ee83ce210282
500
Experimental Immunology, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
2011-04-14T09:34:46Z
2011-04-14T09:34:46Z
2011
To be or not to be a Treg cell: lineage decisions controlled by epigenetic mechanisms. 2011, 4 (158):pe4 Sci Signal
1937-9145
21285410
10.1126/scisignal.2001783
http://hdl.handle.net/10033/128113
Science signaling
Regulatory T (T(reg)) cells are a unique CD4(+) T cell lineage that plays a crucial role in the maintenance of immunological tolerance. The Forkhead box transcription factor Foxp3 is critically involved in T(reg) cell development and responsible for determining the suppressive function of these cells. The majority of Foxp3(+) T(reg) cells are generated during T cell development within the thymus and show features of a stable T cell lineage. New work indicates that both induction and stabilization of Foxp3 expression are under epigenetic control, which suggests that selective interference with the underlying chromatin remodeling mechanisms might enable the development of future therapeutic strategies targeting T(reg) cells.
en
To be or not to be a Treg cell: lineage decisions controlled by epigenetic mechanisms.
Article
2018-06-13T09:18:41Z
Regulatory T (T(reg)) cells are a unique CD4(+) T cell lineage that plays a crucial role in the maintenance of immunological tolerance. The Forkhead box transcription factor Foxp3 is critically involved in T(reg) cell development and responsible for determining the suppressive function of these cells. The majority of Foxp3(+) T(reg) cells are generated during T cell development within the thymus and show features of a stable T cell lineage. New work indicates that both induction and stabilization of Foxp3 expression are under epigenetic control, which suggests that selective interference with the underlying chromatin remodeling mechanisms might enable the development of future therapeutic strategies targeting T(reg) cells.
ORIGINAL
Toker_Hühn_final.pdf
Toker_Hühn_final.pdf
Puplisher's issued reprint
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oai:hzi.openrepository.com:10033/128113
2019-08-30 11:36:32.985
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/1328502019-08-30T11:37:00Zcom_10033_128109col_10033_128110
Hubert, Sandra
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500
Rissiek, Björn
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500
Klages, Katjana
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500
Huehn, Jochen
81855dd40035a02edad8ee83ce210282
500
Sparwasser, Tim
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500
Haag, Friedrich
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500
Koch-Nolte, Friedrich
e2f8c1903f8d46d441711e9af964f048
500
Boyer, Olivier
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500
Seman, Michel
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500
Adriouch, Sahil
303c6184c1f898902710b761eb2cb510
500
Institut National de la Santé et de la Recherche Medicale, U905, 76183 Rouen, France.
2011-06-09T10:50:03Z
2011-06-09T10:50:03Z
2010-11-22
Extracellular NAD+ shapes the Foxp3+ regulatory T cell compartment through the ART2-P2X7 pathway. 2010, 207 (12):2561-8 J. Exp. Med.
1540-9538
20975043
10.1084/jem.20091154
http://hdl.handle.net/10033/132850
The Journal of experimental medicine
CD4(+)CD25(+)FoxP3(+) regulatory T cells (T reg cells) play a major role in the control of immune responses but the factors controlling their homeostasis and function remain poorly characterized. Nicotinamide adenine dinucleotide (NAD(+)) released during cell damage or inflammation results in ART2.2-mediated ADP-ribosylation of the cytolytic P2X7 receptor on T cells. We show that T reg cells express the ART2.2 enzyme and high levels of P2X7 and that T reg cells can be depleted by intravenous injection of NAD(+). Moreover, lower T reg cell numbers are found in mice deficient for the NAD-hydrolase CD38 than in wild-type, P2X7-deficient, or ART2-deficient mice, indicating a role for extracellular NAD(+) in T reg cell homeostasis. Even routine cell preparation leads to release of NAD(+) in sufficient quantities to profoundly affect T reg cell viability, phenotype, and function. We demonstrate that T reg cells can be protected from the deleterious effects of NAD(+) by an inhibitory ART2.2-specific single domain antibody. Furthermore, selective depletion of T reg cells by systemic administration of NAD(+) can be used to promote an antitumor response in several mouse tumor models. Collectively, our data demonstrate that NAD(+) influences survival, phenotype, and function of T reg cells and provide proof of principle that acting on the ART2-P2X7 pathway represents a new strategy to manipulate T reg cells in vivo.
en
ADP Ribose Transferases
Animals
Apoptosis
Forkhead Transcription Factors
L-Selectin
Mice
Mice, Inbred C57BL
NAD
Phosphatidylserines
Receptors, Purinergic P2X7
Signal Transduction
T-Lymphocytes, Regulatory
Extracellular NAD+ shapes the Foxp3+ regulatory T cell compartment through the ART2-P2X7 pathway.
Article
2018-06-13T01:02:13Z
CD4(+)CD25(+)FoxP3(+) regulatory T cells (T reg cells) play a major role in the control of immune responses but the factors controlling their homeostasis and function remain poorly characterized. Nicotinamide adenine dinucleotide (NAD(+)) released during cell damage or inflammation results in ART2.2-mediated ADP-ribosylation of the cytolytic P2X7 receptor on T cells. We show that T reg cells express the ART2.2 enzyme and high levels of P2X7 and that T reg cells can be depleted by intravenous injection of NAD(+). Moreover, lower T reg cell numbers are found in mice deficient for the NAD-hydrolase CD38 than in wild-type, P2X7-deficient, or ART2-deficient mice, indicating a role for extracellular NAD(+) in T reg cell homeostasis. Even routine cell preparation leads to release of NAD(+) in sufficient quantities to profoundly affect T reg cell viability, phenotype, and function. We demonstrate that T reg cells can be protected from the deleterious effects of NAD(+) by an inhibitory ART2.2-specific single domain antibody. Furthermore, selective depletion of T reg cells by systemic administration of NAD(+) can be used to promote an antitumor response in several mouse tumor models. Collectively, our data demonstrate that NAD(+) influences survival, phenotype, and function of T reg cells and provide proof of principle that acting on the ART2-P2X7 pathway represents a new strategy to manipulate T reg cells in vivo.
ORIGINAL
Hubert et al_final.pdf
Hubert et al_final.pdf
allowed publisher's PDF
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THUMBNAIL
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oai:hzi.openrepository.com:10033/132850
2019-08-30 11:37:00.012
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/3053872019-08-30T11:37:44Zcom_10033_128109col_10033_128110
Sledzińska, Anna
862618b53cd811165f1c29ac76b0906c
500
Hemmers, Saskia
ee8dc2641c072c12c7af2c1bc1790807
500
Mair, Florian
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500
Gorka, Oliver
f07deaedc6dfcdc274494171638ffafc
500
Ruland, Jürgen
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500
Fairbairn, Lynsey
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500
Nissler, Anja
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Müller, Werner
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500
Waisman, Ari
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500
Becher, Burkhard
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Buch, Thorsten
b6a2e8e81e82a1b249a15f3aa2d72be3
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Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
2013-11-14T11:04:02Z
2013-11-14T11:04:02Z
2013-10
TGF-β Signalling Is Required for CD4(+) T Cell Homeostasis But Dispensable for Regulatory T Cell Function. 2013, 11 (10):e1001674 PLoS Biol.
1545-7885
24115907
10.1371/journal.pbio.1001674
http://hdl.handle.net/10033/305387
PLoS biology
TGF-β is widely held to be critical for the maintenance and function of regulatory T (Treg) cells and thus peripheral tolerance. This is highlighted by constitutive ablation of TGF-β receptor (TR) during thymic development in mice, which leads to a lethal autoimmune syndrome. Here we describe that TGF-β-driven peripheral tolerance is not regulated by TGF-β signalling on mature CD4(+) T cells. Inducible TR2 ablation specifically on CD4(+) T cells did not result in a lethal autoinflammation. Transfer of these TR2-deficient CD4(+) T cells to lymphopenic recipients resulted in colitis, but not overt autoimmunity. In contrast, thymic ablation of TR2 in combination with lymphopenia led to lethal multi-organ inflammation. Interestingly, deletion of TR2 on mature CD4(+) T cells does not result in the collapse of the Treg cell population as observed in constitutive models. Instead, a pronounced enlargement of both regulatory and effector memory T cell pools was observed. This expansion is cell-intrinsic and seems to be caused by increased T cell receptor sensitivity independently of common gamma chain-dependent cytokine signals. The expression of Foxp3 and other regulatory T cells markers was not dependent on TGF-β signalling and the TR2-deficient Treg cells retained their suppressive function both in vitro and in vivo. In summary, absence of TGF-β signalling on mature CD4(+) T cells is not responsible for breakdown of peripheral tolerance, but rather controls homeostasis of mature T cells in adult mice.
en
Archived with thanks to PLoS biology
TGF-β Signalling Is Required for CD4(+) T Cell Homeostasis But Dispensable for Regulatory T Cell Function.
Article
2018-06-12T17:34:27Z
TGF-β is widely held to be critical for the maintenance and function of regulatory T (Treg) cells and thus peripheral tolerance. This is highlighted by constitutive ablation of TGF-β receptor (TR) during thymic development in mice, which leads to a lethal autoimmune syndrome. Here we describe that TGF-β-driven peripheral tolerance is not regulated by TGF-β signalling on mature CD4(+) T cells. Inducible TR2 ablation specifically on CD4(+) T cells did not result in a lethal autoinflammation. Transfer of these TR2-deficient CD4(+) T cells to lymphopenic recipients resulted in colitis, but not overt autoimmunity. In contrast, thymic ablation of TR2 in combination with lymphopenia led to lethal multi-organ inflammation. Interestingly, deletion of TR2 on mature CD4(+) T cells does not result in the collapse of the Treg cell population as observed in constitutive models. Instead, a pronounced enlargement of both regulatory and effector memory T cell pools was observed. This expansion is cell-intrinsic and seems to be caused by increased T cell receptor sensitivity independently of common gamma chain-dependent cytokine signals. The expression of Foxp3 and other regulatory T cells markers was not dependent on TGF-β signalling and the TR2-deficient Treg cells retained their suppressive function both in vitro and in vivo. In summary, absence of TGF-β signalling on mature CD4(+) T cells is not responsible for breakdown of peripheral tolerance, but rather controls homeostasis of mature T cells in adult mice.
ORIGINAL
sledzinska at al_final.pdf
sledzinska at al_final.pdf
Open Access publication
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Helmholtz Zentrum für Infektionsforschung Repository
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Fernandez, Marylise
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Brück, Wolfgang
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Steinbach, Karin
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Vorm, Mariann
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Coras, Roland
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Blümcke, Ingmar
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Bonilla, Weldy V
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Fleige, Anne
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Forman, Ruth
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Müller, Werner
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Becher, Burkhard
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Misgeld, Thomas
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Kerschensteiner, Martin
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Pinschewer, Daniel D
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Merkler, Doron
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Department of Pathology and Immunology and 2 World Health Organization Collaborating Centre for Vaccine Immunology, University of Geneva, 1211 Geneva, Switzerland.
2013-12-03T13:57:21Z
2013-12-03T13:57:21Z
2013-09-23
Neuroprotective intervention by interferon-γ blockade prevents CD8+ T cell-mediated dendrite and synapse loss. 2013, 210 (10):2087-103 J. Exp. Med.
1540-9538
23999498
10.1084/jem.20122143
http://hdl.handle.net/10033/306168
The Journal of experimental medicine
Neurons are postmitotic and thus irreplaceable cells of the central nervous system (CNS). Accordingly, CNS inflammation with resulting neuronal damage can have devastating consequences. We investigated molecular mediators and structural consequences of CD8(+) T lymphocyte (CTL) attack on neurons in vivo. In a viral encephalitis model in mice, disease depended on CTL-derived interferon-γ (IFN-γ) and neuronal IFN-γ signaling. Downstream STAT1 phosphorylation and nuclear translocation in neurons were associated with dendrite and synapse loss (deafferentation). Analogous molecular and structural alterations were also found in human Rasmussen encephalitis, a CTL-mediated human autoimmune disorder of the CNS. Importantly, therapeutic intervention by IFN-γ blocking antibody prevented neuronal deafferentation and clinical disease without reducing CTL responses or CNS infiltration. These findings identify neuronal IFN-γ signaling as a novel target for neuroprotective interventions in CTL-mediated CNS disease.
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Archived with thanks to The Journal of experimental medicine
Adolescent
Adult
Animals
Antigens, CD95
CD8-Positive T-Lymphocytes
Cell Nucleus
Child
Dendrites
Humans
Interferon-gamma
Lymphocytic Choriomeningitis
Lymphocytic choriomeningitis virus
Mice
Mice, Transgenic
Neurons
Perforin
Phosphorylation
Protein Transport
Receptors, Interferon
STAT1 Transcription Factor
Signal Transduction
Spinal Cord
Synapses
T-Lymphocytes, Cytotoxic
Young Adult
Neuroprotective intervention by interferon-γ blockade prevents CD8+ T cell-mediated dendrite and synapse loss.
Article
2018-06-13T15:47:45Z
Neurons are postmitotic and thus irreplaceable cells of the central nervous system (CNS). Accordingly, CNS inflammation with resulting neuronal damage can have devastating consequences. We investigated molecular mediators and structural consequences of CD8(+) T lymphocyte (CTL) attack on neurons in vivo. In a viral encephalitis model in mice, disease depended on CTL-derived interferon-γ (IFN-γ) and neuronal IFN-γ signaling. Downstream STAT1 phosphorylation and nuclear translocation in neurons were associated with dendrite and synapse loss (deafferentation). Analogous molecular and structural alterations were also found in human Rasmussen encephalitis, a CTL-mediated human autoimmune disorder of the CNS. Importantly, therapeutic intervention by IFN-γ blocking antibody prevented neuronal deafferentation and clinical disease without reducing CTL responses or CNS infiltration. These findings identify neuronal IFN-γ signaling as a novel target for neuroprotective interventions in CTL-mediated CNS disease.
ORIGINAL
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Kreutzfeld et al_final.pdf.txt
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10033/306168
oai:hzi.openrepository.com:10033/306168
2019-08-30 11:37:44.775
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/3229042019-08-30T11:34:48Zcom_10033_128109col_10033_128110
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Löhr, Kirsten
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Floess, Stefan
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Zimmermann, Julian
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Ulrich, Reiner
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Baumgärtner, Wolfgang
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2014-07-14T14:20:28Z
2014-07-14T14:20:28Z
2014-03
Effector molecules released by Th1 but not Th17 cells drive an M1 response in microglia. 2014, 37:248-59 Brain Behav. Immun.
1090-2139
24412213
10.1016/j.bbi.2014.01.001
http://hdl.handle.net/10033/322904
Brain, behavior, and immunity
Microglia act as sensors of inflammation in the central nervous system (CNS) and respond to many stimuli. Other key players in neuroinflammatory diseases are CD4+ T helper cell (Th) subsets that characteristically secrete IFN-γ (Th1) or IL-17 (Th17). However, the potential of a distinct cytokine milieu generated by these effector T cell subsets to modulate microglial phenotype and function is poorly understood. We therefore investigated the ability of factors secreted by Th1 and Th17 cells to induce microglial activation. In vitro experiments wherein microglia were cultured in the presence of supernatants derived from polarized Th1 or Th17 cultures, revealed that Th1-associated factors could directly activate and trigger a proinflammatory M1-type gene expression profile in microglia that was cell-cell contact independent, whereas Th17 cells or its associated factors did not have any direct influence on microglia. To assess the effects of the key Th17 effector cytokine IL-17A in vivo we used transgenic mice in which IL-17A is specifically expressed in astrocytes. Flow cytometric and histological analysis revealed only subtle changes in the phenotype of microglia suggesting only minimal effects of constitutively produced IL-17A on microglia in vivo. Neither IL-23 signaling nor addition of GM-CSF, a recently described effector molecule of Th17 cells, changed the incapacity of Th17 cells to activate microglia. These findings demonstrate a potent effect of Th1 cells on microglia, however, the mechanism of how Th17 cells achieve their effect in CNS inflammation remains unclear.
en
Archived with thanks to Brain, behavior, and immunity
Effector molecules released by Th1 but not Th17 cells drive an M1 response in microglia.
Article
2018-06-12T21:29:11Z
Microglia act as sensors of inflammation in the central nervous system (CNS) and respond to many stimuli. Other key players in neuroinflammatory diseases are CD4+ T helper cell (Th) subsets that characteristically secrete IFN-γ (Th1) or IL-17 (Th17). However, the potential of a distinct cytokine milieu generated by these effector T cell subsets to modulate microglial phenotype and function is poorly understood. We therefore investigated the ability of factors secreted by Th1 and Th17 cells to induce microglial activation. In vitro experiments wherein microglia were cultured in the presence of supernatants derived from polarized Th1 or Th17 cultures, revealed that Th1-associated factors could directly activate and trigger a proinflammatory M1-type gene expression profile in microglia that was cell-cell contact independent, whereas Th17 cells or its associated factors did not have any direct influence on microglia. To assess the effects of the key Th17 effector cytokine IL-17A in vivo we used transgenic mice in which IL-17A is specifically expressed in astrocytes. Flow cytometric and histological analysis revealed only subtle changes in the phenotype of microglia suggesting only minimal effects of constitutively produced IL-17A on microglia in vivo. Neither IL-23 signaling nor addition of GM-CSF, a recently described effector molecule of Th17 cells, changed the incapacity of Th17 cells to activate microglia. These findings demonstrate a potent effect of Th1 cells on microglia, however, the mechanism of how Th17 cells achieve their effect in CNS inflammation remains unclear.
ORIGINAL
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Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/3238062019-08-30T11:35:39Zcom_10033_128109col_10033_128110
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Curotto de Lafaille, Maria A
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Xiong, Huizhong
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Dolpady, Jayashree
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Frey, Alan B
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Ruocco, Maria Grazia
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Yang, Yi
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Floess, Stefan
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Huehn, Jochen
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Oh, Soyoung
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Li, Ming O
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Niec, Rachel E
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Rudensky, Alexander Y
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Dustin, Michael L
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Lafaille, Juan J
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2014-07-25T09:24:02Z
2014-07-25T09:24:02Z
2012-09-24
Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells. 2012, 209 (10):1723-42, S1 J. Exp. Med.
1540-9538
22966001
10.1084/jem.20120914
http://hdl.handle.net/10033/323806
The Journal of experimental medicine
Foxp3 activity is essential for the normal function of the immune system. Two types of regulatory T (T reg) cells express Foxp3, thymus-generated natural T reg (nT reg) cells, and peripherally generated adaptive T reg (iT reg) cells. These cell types have complementary functions. Until now, it has not been possible to distinguish iT reg from nT reg cells in vivo based solely on surface markers. We report here that Neuropilin 1 (Nrp1) is expressed at high levels by most nT reg cells; in contrast, mucosa-generated iT reg and other noninflammatory iT reg cells express low levels of Nrp1. We found that Nrp1 expression is under the control of TGF-β. By tracing nT reg and iT reg cells, we could establish that some tumors have a very large proportion of infiltrating iT reg cells. iT reg cells obtained from highly inflammatory environments, such as the spinal cords of mice with spontaneous autoimmune encephalomyelitis (EAE) and the lungs of mice with chronic asthma, express Nrp1. In the same animals, iT reg cells in secondary lymphoid organs remain Nrp1(low). We also determined that, in spontaneous EAE, iT reg cells help to establish a chronic phase of the disease.
en
Archived with thanks to The Journal of experimental medicine
Animals
Cell Lineage
Cell Membrane
Forkhead Transcription Factors
Gene Expression Regulation
Inflammation
Intestines
Lymphocyte Activation
Lymphocytes, Tumor-Infiltrating
Metagenome
Mice
Mice, Transgenic
Mucous Membrane
Neuropilin-1
T-Lymphocytes, Regulatory
Thymus Gland
Transforming Growth Factor beta
Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells.
Article
2018-06-12T16:58:50Z
Foxp3 activity is essential for the normal function of the immune system. Two types of regulatory T (T reg) cells express Foxp3, thymus-generated natural T reg (nT reg) cells, and peripherally generated adaptive T reg (iT reg) cells. These cell types have complementary functions. Until now, it has not been possible to distinguish iT reg from nT reg cells in vivo based solely on surface markers. We report here that Neuropilin 1 (Nrp1) is expressed at high levels by most nT reg cells; in contrast, mucosa-generated iT reg and other noninflammatory iT reg cells express low levels of Nrp1. We found that Nrp1 expression is under the control of TGF-β. By tracing nT reg and iT reg cells, we could establish that some tumors have a very large proportion of infiltrating iT reg cells. iT reg cells obtained from highly inflammatory environments, such as the spinal cords of mice with spontaneous autoimmune encephalomyelitis (EAE) and the lungs of mice with chronic asthma, express Nrp1. In the same animals, iT reg cells in secondary lymphoid organs remain Nrp1(low). We also determined that, in spontaneous EAE, iT reg cells help to establish a chronic phase of the disease.
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2019-08-30 11:35:39.597
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/3250882019-08-30T11:35:39Zcom_10033_128109col_10033_128110
Steinfelder, Svenja
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Floess, Stefan
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Engelbert, Dirk
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Haeringer, Barbara
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Baron, Udo
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Rivino, Laura
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Steckel, Bodo
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Gruetzkau, Andreas
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Olek, Sven
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Geginat, Jens
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Huehn, Jochen
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Hamann, Alf
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Dept. of experimental immunology, Helmholtz Centre for infection reseach, Inhoffenstr. 7, D38124 Braunschweig, Germany.
2014-08-22T13:02:39Z
2014-08-22T13:02:39Z
2011-03-10
Epigenetic modification of the human CCR6 gene is associated with stable CCR6 expression in T cells. 2011, 117 (10):2839-46 Blood
1528-0020
21228329
10.1182/blood-2010-06-293027
http://hdl.handle.net/10033/325088
Blood
CCR6 is a chemokine receptor expressed on Th17 cells and regulatory T cells that is induced by T-cell priming with certain cytokines, but how its expression and stability are regulated at the molecular level is largely unknown. Here, we identified and characterized a noncoding region of the human CCR6 locus that displayed unmethylated CpG motifs (differentially methylated region [DMR]) selectively in CCR6(+) lymphocytes. CCR6 expression on circulating CD4(+) T cells was stable on cytokine-induced proliferation but partially down-regulated on T-cell receptor stimulation. However, CCR6 down-regulation was mostly transient, and the DMR within the CCR6 locus remained demethylated. Notably, in vitro induction of CCR6 expression with cytokines in T-cell receptor-activated naive CD4(+) T cells was not associated with a demethylated DMR and resulted in unstable CCR6 expression. Conversely, treatment with the DNA methylation inhibitor 5'-azacytidine induced demethylation of the DMR and led to increased and stable CCR6 expression. Finally, when cloned into a reporter gene plasmid, the DMR displayed transcriptional activity in memory T cells that was suppressed by DNA methylation. In summary, we have identified a noncoding region of the human CCR6 gene with methylation-sensitive transcriptional activity in CCR6(+) T cells that controls stable CCR6 expression via epigenetic mechanisms.
en
Archived with thanks to Blood
Cell Separation
DNA Methylation
Epigenesis, Genetic
Flow Cytometry
Gene Expression
Gene Expression Regulation
Humans
Polymerase Chain Reaction
Receptors, CCR6
T-Lymphocytes
Transfection
Epigenetic modification of the human CCR6 gene is associated with stable CCR6 expression in T cells.
Article
2018-06-13T07:25:41Z
CCR6 is a chemokine receptor expressed on Th17 cells and regulatory T cells that is induced by T-cell priming with certain cytokines, but how its expression and stability are regulated at the molecular level is largely unknown. Here, we identified and characterized a noncoding region of the human CCR6 locus that displayed unmethylated CpG motifs (differentially methylated region [DMR]) selectively in CCR6(+) lymphocytes. CCR6 expression on circulating CD4(+) T cells was stable on cytokine-induced proliferation but partially down-regulated on T-cell receptor stimulation. However, CCR6 down-regulation was mostly transient, and the DMR within the CCR6 locus remained demethylated. Notably, in vitro induction of CCR6 expression with cytokines in T-cell receptor-activated naive CD4(+) T cells was not associated with a demethylated DMR and resulted in unstable CCR6 expression. Conversely, treatment with the DNA methylation inhibitor 5'-azacytidine induced demethylation of the DMR and led to increased and stable CCR6 expression. Finally, when cloned into a reporter gene plasmid, the DMR displayed transcriptional activity in memory T cells that was suppressed by DNA methylation. In summary, we have identified a noncoding region of the human CCR6 gene with methylation-sensitive transcriptional activity in CCR6(+) T cells that controls stable CCR6 expression via epigenetic mechanisms.
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Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/3337032019-08-30T11:28:23Zcom_10033_128109col_10033_128110
Schreiber, Lisa
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500
Pietzsch, Beate
b31ea86b6387d5b14ae72d1fe3614091
500
Floess, Stefan
5ffe089d50f6ea39d568657c60ebcc8f
500
Farah, Carla
5b612b08e22ac82a839e4dd74852d4e8
500
Jänsch, Lothar
14cc18542edf57a7b25c4b0c14a8c05a
600
http://orcid.org/0000-0002-5655-1181
Schmitz, Ingo
d064a965762a0bd3539b3090354dba25
600
http://orcid.org/0000-0002-5360-0419
Huehn, Jochen
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500
Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
2014-11-04T14:44:26Z
2014-11-04T14:44:26Z
2014
The Treg-specific demethylated region stabilizes Foxp3 expression independently of NF-κB signaling. 2014, 9 (2):e88318 PLoS ONE
1932-6203
24505473
10.1371/journal.pone.0088318
http://hdl.handle.net/10033/333703
PloS one
Regulatory T cells (Tregs) obtain immunosuppressive capacity by the upregulation of forkhead box protein 3 (Foxp3), and persistent expression of this transcription factor is required to maintain their immune regulatory function and ensure immune homeostasis. Stable Foxp3 expression is achieved through epigenetic modification of the Treg-specific demethylated region (TSDR), an evolutionarily conserved non-coding element within the Foxp3 gene locus. Here, we present molecular data suggesting that TSDR enhancer activity is restricted to T cells and cannot be induced in other immune cells such as macrophages or B cells. Since NF-κB signaling has been reported to be instrumental to induce Foxp3 expression during Treg development, we analyzed how NF-κB factors are involved in the molecular regulation of the TSDR. Unexpectedly, we neither observed transcriptional activity of a previously postulated NF-κB binding site within the TSDR nor did the entire TSDR show any transcriptional responsiveness to NF-κB activation at all. Finally, the NF-κB subunit c-Rel revealed to be dispensable for epigenetic imprinting of sustained Foxp3 expression by TSDR demethylation. In conclusion, we show that NF-κB signaling is not substantially involved in TSDR-mediated stabilization of Foxp3 expression in Tregs.
en
Animals
Cell Line, Tumor
DNA Methylation
Forkhead Transcription Factors
Gene Expression Regulation
Genetic Loci
Mice
Mice, Inbred C57BL
NF-kappa B
Signal Transduction
T-Lymphocytes, Regulatory
The Treg-specific demethylated region stabilizes Foxp3 expression independently of NF-κB signaling.
Article
2018-06-13T15:33:16Z
Regulatory T cells (Tregs) obtain immunosuppressive capacity by the upregulation of forkhead box protein 3 (Foxp3), and persistent expression of this transcription factor is required to maintain their immune regulatory function and ensure immune homeostasis. Stable Foxp3 expression is achieved through epigenetic modification of the Treg-specific demethylated region (TSDR), an evolutionarily conserved non-coding element within the Foxp3 gene locus. Here, we present molecular data suggesting that TSDR enhancer activity is restricted to T cells and cannot be induced in other immune cells such as macrophages or B cells. Since NF-κB signaling has been reported to be instrumental to induce Foxp3 expression during Treg development, we analyzed how NF-κB factors are involved in the molecular regulation of the TSDR. Unexpectedly, we neither observed transcriptional activity of a previously postulated NF-κB binding site within the TSDR nor did the entire TSDR show any transcriptional responsiveness to NF-κB activation at all. Finally, the NF-κB subunit c-Rel revealed to be dispensable for epigenetic imprinting of sustained Foxp3 expression by TSDR demethylation. In conclusion, we show that NF-κB signaling is not substantially involved in TSDR-mediated stabilization of Foxp3 expression in Tregs.
ORIGINAL
Schreiber et al_final.pdf
Schreiber et al_final.pdf
Open Access publication
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Schreiber et al_final.pdf.txt
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oai:hzi.openrepository.com:10033/333703
2019-08-30 11:28:23.89
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/3462052019-08-30T11:37:23Zcom_10033_128109col_10033_128110
Mayer, Christian T
9ce4ba604b1f0b5f7332500a34620f9d
500
Floess, Stefan
5ffe089d50f6ea39d568657c60ebcc8f
500
Baru, Abdul Mannan
99c53206316158a8aa847c008f333f68
500
Lahl, Katharina
6e4ac17cd12c7bd8381e8524bcbe9de8
500
Huehn, Jochen
81855dd40035a02edad8ee83ce210282
500
Sparwasser, Tim
b9a321f14389c2eaffa0abc915b958bf
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2015-03-05T12:16:49Z
2015-03-05T12:16:49Z
2011-03
CD8+ Foxp3+ T cells share developmental and phenotypic features with classical CD4+ Foxp3+ regulatory T cells but lack potent suppressive activity. 2011, 41 (3):716-25 Eur. J. Immunol.
1521-4141
21312192
10.1002/eji.201040913
http://hdl.handle.net/10033/346205
European journal of immunology
"Suppressor T cells" were historically defined within the CD8(+) T-cell compartment and recent studies have highlighted several naturally occurring CD8(+) Foxp3(-) Treg populations. However, the relevance of CD8(+) Foxp3(+) T cells, which represent a minor population in both thymi and secondary lymphoid organs of nonmanipulated mice, remains unclear. We here demonstrate that de novo Foxp3 induction in peripheral CD8(+) Foxp3(-) T cells is counter-regulated by DC-mediated co-stimulation via CD80/CD86. CD8(+) Foxp3(+) T cells fail to develop in TCR-transgenic mice with Rag1(-/-) background, similar to classical CD4(+) Foxp3(+) Tregs. Notably, both naturally occurring and induced CD8(+) Foxp3(+) T cells express bona fide Treg markers including CD25, GITR, CTLA4 and CD103, and show defective IFN-γ production upon restimulation when compared with their CD8(+) Foxp3(-) counterparts. However, utilizing DEREG transgenic mice for the isolation of Foxp3(+) cells by eGFP reporter expression, we demonstrate that induced CD8(+) Foxp3(+) T cells similar to activated CD8(+) Foxp3(-) T cells only mildly suppress T-cell proliferation and IFN-γ production. We therefore categorize CD8(+) Foxp3(+) T cells as a tightly controlled population sharing certain developmental and phenotypic properties with classical CD4(+) Foxp3(+) Tregs, but lacking potent suppressive activity.
en
Animals
Antigens, CD28
Antigens, CD80
Antigens, CD86
CD8-Positive T-Lymphocytes
Cell Differentiation
Cell Proliferation
Dendritic Cells
Forkhead Transcription Factors
In Vitro Techniques
Interferon-gamma
Lymphocyte Activation
Male
Mice
Mice, Knockout
Mice, Transgenic
Phenotype
Receptors, Antigen, T-Cell
Signal Transduction
T-Lymphocyte Subsets
T-Lymphocytes, Regulatory
Transforming Growth Factor beta
CD8+ Foxp3+ T cells share developmental and phenotypic features with classical CD4+ Foxp3+ regulatory T cells but lack potent suppressive activity.
Article
2018-06-13T00:28:37Z
"Suppressor T cells" were historically defined within the CD8(+) T-cell compartment and recent studies have highlighted several naturally occurring CD8(+) Foxp3(-) Treg populations. However, the relevance of CD8(+) Foxp3(+) T cells, which represent a minor population in both thymi and secondary lymphoid organs of nonmanipulated mice, remains unclear. We here demonstrate that de novo Foxp3 induction in peripheral CD8(+) Foxp3(-) T cells is counter-regulated by DC-mediated co-stimulation via CD80/CD86. CD8(+) Foxp3(+) T cells fail to develop in TCR-transgenic mice with Rag1(-/-) background, similar to classical CD4(+) Foxp3(+) Tregs. Notably, both naturally occurring and induced CD8(+) Foxp3(+) T cells express bona fide Treg markers including CD25, GITR, CTLA4 and CD103, and show defective IFN-γ production upon restimulation when compared with their CD8(+) Foxp3(-) counterparts. However, utilizing DEREG transgenic mice for the isolation of Foxp3(+) cells by eGFP reporter expression, we demonstrate that induced CD8(+) Foxp3(+) T cells similar to activated CD8(+) Foxp3(-) T cells only mildly suppress T-cell proliferation and IFN-γ production. We therefore categorize CD8(+) Foxp3(+) T cells as a tightly controlled population sharing certain developmental and phenotypic properties with classical CD4(+) Foxp3(+) Tregs, but lacking potent suppressive activity.
ORIGINAL
mayer et al_final.pdf
mayer et al_final.pdf
Open Access publication
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mayer et al_final.pdf.txt
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THUMBNAIL
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2019-08-30 11:37:23.854
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/5657742019-08-30T11:28:23Zcom_10033_128109col_10033_128110
Yang, Bi-Huei
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Floess, Stefan
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Hagemann, Stefanie
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Deyneko, Igor V
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Groebe, Lothar
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Pezoldt, Joern
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Sparwasser, Tim
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http://orcid.org/0000-0001-5645-902X
Lochner, Matthias
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Huehn, Jochen
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Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2015-08-10T09:03:06Z
2015-08-10T09:03:06Z
2015-02-18
Development of a unique epigenetic signature during in vivo Th17 differentiation. 2015, 43 (3):1537-48 Nucleic Acids Res.
1362-4962
25593324
10.1093/nar/gkv014
http://hdl.handle.net/10033/565774
Nucleic acids research
Activated naive CD4(+) T cells are highly plastic cells that can differentiate into various T helper (Th) cell fates characterized by the expression of effector cytokines like IFN-γ (Th1), IL-4 (Th2) or IL-17A (Th17). Although previous studies have demonstrated that epigenetic mechanisms including DNA demethylation can stabilize effector cytokine expression, a comprehensive analysis of the changes in the DNA methylation pattern during differentiation of naive T cells into Th cell subsets is lacking. Hence, we here performed a genome-wide methylome analysis of ex vivo isolated naive CD4(+) T cells, Th1 and Th17 cells. We could demonstrate that naive CD4(+) T cells share more demethylated regions with Th17 cells when compared to Th1 cells, and that overall Th17 cells display the highest number of demethylated regions, findings which are in line with the previously reported plasticity of Th17 cells. We could identify seven regions located in Il17a, Zfp362, Ccr6, Acsbg1, Dpp4, Rora and Dclk1 showing pronounced demethylation selectively in ex vivo isolated Th17 cells when compared to other ex vivo isolated Th cell subsets and in vitro generated Th17 cells, suggesting that this unique epigenetic signature allows identifying and functionally characterizing in vivo generated Th17 cells.
en
Animals
Cell Differentiation
DNA Methylation
Epigenesis, Genetic
Female
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Oligonucleotide Array Sequence Analysis
Th17 Cells
Development of a unique epigenetic signature during in vivo Th17 differentiation.
Article
2018-06-12T22:25:29Z
Activated naive CD4(+) T cells are highly plastic cells that can differentiate into various T helper (Th) cell fates characterized by the expression of effector cytokines like IFN-γ (Th1), IL-4 (Th2) or IL-17A (Th17). Although previous studies have demonstrated that epigenetic mechanisms including DNA demethylation can stabilize effector cytokine expression, a comprehensive analysis of the changes in the DNA methylation pattern during differentiation of naive T cells into Th cell subsets is lacking. Hence, we here performed a genome-wide methylome analysis of ex vivo isolated naive CD4(+) T cells, Th1 and Th17 cells. We could demonstrate that naive CD4(+) T cells share more demethylated regions with Th17 cells when compared to Th1 cells, and that overall Th17 cells display the highest number of demethylated regions, findings which are in line with the previously reported plasticity of Th17 cells. We could identify seven regions located in Il17a, Zfp362, Ccr6, Acsbg1, Dpp4, Rora and Dclk1 showing pronounced demethylation selectively in ex vivo isolated Th17 cells when compared to other ex vivo isolated Th cell subsets and in vitro generated Th17 cells, suggesting that this unique epigenetic signature allows identifying and functionally characterizing in vivo generated Th17 cells.
ORIGINAL
Yang et al_final.pdf
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2019-08-30 11:28:23.746
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6209522019-08-30T11:27:16Zcom_10033_128109col_10033_128110
Prajeeth, Chittappen K
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500
Beineke, Andreas
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Iskandar, Cut D
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Gudi, Viktoria
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Herder, Vanessa
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Gerhauser, Ingo
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Haist, Verena
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Teich, René
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Huehn, Jochen
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Baumgärtner, Wolfgang
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Stangel, Martin
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2017-06-15T10:30:24Z
2017-06-15T10:30:24Z
2014-11-13
2015-09-04T08:23:52Z
Journal of Neuroinflammation. 2014 Nov 13;11(1):180
http://dx.doi.org/10.1186/s12974-014-0180-9
http://hdl.handle.net/10033/620952
Abstract Background Theiler’s murine encephalomyelitis virus (TMEV) infection represents a commonly used infectious animal model to study various aspects of the pathogenesis of multiple sclerosis (MS). In susceptible SJL mice, dominant activity of Foxp3+ CD4+ regulatory T cells (Tregs) in the CNS partly contributes to viral persistence and progressive demyelination. On the other hand, resistant C57BL/6 mice rapidly clear the virus by mounting a strong antiviral immune response. However, very little is known about the role of Tregs in regulating antiviral responses during acute encephalitis in resistant mouse strains. Methods In this study, we used DEREG mice that express the diphtheria toxin (DT) receptor under control of the foxp3 locus to selectively deplete Foxp3+ Tregs by injection of DT prior to infection and studied the effect of Treg depletion on the course of acute Theiler’s murine encephalomyelitis (TME). Results As expected, DEREG mice that are on a C57BL/6 background were resistant to TMEV infection and cleared the virus within days of infection, regardless of the presence or absence of Tregs. Nevertheless, in the absence of Tregs we observed priming of stronger effector T cell responses in the periphery, which subsequently resulted in a transient increase in the frequency of IFNγ-producing T cells in the brain at an early stage of infection. Histological and flow cytometric analysis revealed that this transiently increased frequency of brain-infiltrating IFNγ-producing T cells in Treg-depleted mice neither led to an augmented antiviral response nor enhanced inflammation-mediated tissue damage. Intriguingly, Treg depletion did not change the expression of IL-10 in the infected brain, which might play a role for dampening the inflammatory damage caused by the increased number of effector T cells. Conclusion We therefore propose that unlike susceptible mice strains, interfering with the Treg compartment of resistant mice only has negligible effects on virus-induced pathologies in the CNS. Furthermore, in the absence of Tregs, local anti-inflammatory mechanisms might limit the extent of damage caused by strong anti-viral response in the CNS.
Limited role of regulatory T cells during acute Theiler virus-induced encephalitis in resistant C57BL/6 mice
Journal Article
en
Prajeeth et al.; licensee BioMed Central Ltd.
2018-06-17T03:53:48Z
Abstract
Background
Theiler’s murine encephalomyelitis virus (TMEV) infection represents a commonly used infectious animal model to study various aspects of the pathogenesis of multiple sclerosis (MS). In susceptible SJL mice, dominant activity of Foxp3+ CD4+ regulatory T cells (Tregs) in the CNS partly contributes to viral persistence and progressive demyelination. On the other hand, resistant C57BL/6 mice rapidly clear the virus by mounting a strong antiviral immune response. However, very little is known about the role of Tregs in regulating antiviral responses during acute encephalitis in resistant mouse strains.
Methods
In this study, we used DEREG mice that express the diphtheria toxin (DT) receptor under control of the foxp3 locus to selectively deplete Foxp3+ Tregs by injection of DT prior to infection and studied the effect of Treg depletion on the course of acute Theiler’s murine encephalomyelitis (TME).
Results
As expected, DEREG mice that are on a C57BL/6 background were resistant to TMEV infection and cleared the virus within days of infection, regardless of the presence or absence of Tregs. Nevertheless, in the absence of Tregs we observed priming of stronger effector T cell responses in the periphery, which subsequently resulted in a transient increase in the frequency of IFNγ-producing T cells in the brain at an early stage of infection. Histological and flow cytometric analysis revealed that this transiently increased frequency of brain-infiltrating IFNγ-producing T cells in Treg-depleted mice neither led to an augmented antiviral response nor enhanced inflammation-mediated tissue damage. Intriguingly, Treg depletion did not change the expression of IL-10 in the infected brain, which might play a role for dampening the inflammatory damage caused by the increased number of effector T cells.
Conclusion
We therefore propose that unlike susceptible mice strains, interfering with the Treg compartment of resistant mice only has negligible effects on virus-induced pathologies in the CNS. Furthermore, in the absence of Tregs, local anti-inflammatory mechanisms might limit the extent of damage caused by strong anti-viral response in the CNS.
ORIGINAL
12974_2014_Article_180.pdf
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Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/5935462019-08-30T11:36:32Zcom_10033_128109col_10033_128110
Prajeeth, Chittappen K
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Beineke, Andreas
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Iskandar, Cut Dahlia
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Gudi, Viktoria
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Herder, Vanessa
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Gerhauser, Ingo
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Haist, Verena
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Teich, René
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Huehn, Jochen
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Baumgärtner, Wolfgang
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Stangel, Martin
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Helmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany.
2016-01-15T14:12:36Z
2016-01-15T14:12:36Z
2014
Limited role of regulatory T cells during acute Theiler virus-induced encephalitis in resistant C57BL/6 mice. 2014, 11:180 J Neuroinflammation
1742-2094
25391297
10.1186/s12974-014-0180-9
http://hdl.handle.net/10033/593546
Journal of neuroinflammation
Theiler's murine encephalomyelitis virus (TMEV) infection represents a commonly used infectious animal model to study various aspects of the pathogenesis of multiple sclerosis (MS). In susceptible SJL mice, dominant activity of Foxp3(+) CD4(+) regulatory T cells (Tregs) in the CNS partly contributes to viral persistence and progressive demyelination. On the other hand, resistant C57BL/6 mice rapidly clear the virus by mounting a strong antiviral immune response. However, very little is known about the role of Tregs in regulating antiviral responses during acute encephalitis in resistant mouse strains.
en
Acute Disease
Animals
Cardiovirus Infections
Disease Resistance
Encephalitis, Viral
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
T-Lymphocytes, Regulatory
Theilovirus
Limited role of regulatory T cells during acute Theiler virus-induced encephalitis in resistant C57BL/6 mice.
Article
2018-06-18T08:16:26Z
Theiler's murine encephalomyelitis virus (TMEV) infection represents a commonly used infectious animal model to study various aspects of the pathogenesis of multiple sclerosis (MS). In susceptible SJL mice, dominant activity of Foxp3(+) CD4(+) regulatory T cells (Tregs) in the CNS partly contributes to viral persistence and progressive demyelination. On the other hand, resistant C57BL/6 mice rapidly clear the virus by mounting a strong antiviral immune response. However, very little is known about the role of Tregs in regulating antiviral responses during acute encephalitis in resistant mouse strains.
ORIGINAL
Prejeeth et al.pdf
Prejeeth et al.pdf
Open Access publication
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Prejeeth et al.pdf.txt
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2019-08-30 11:36:32.906
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6004662019-08-30T11:37:44Zcom_10033_128109col_10033_128110
Franckaert, Dean
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500
Dooley, James
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Roos, Evelyne
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Floess, Stefan
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Huehn, Jochen
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Luche, Herve
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Fehling, Hans Joerg
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Liston, Adrian
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Linterman, Michelle A
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Schlenner, Susan M
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Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2016-03-02T11:43:24Z
2016-03-02T11:43:24Z
2015-04
Promiscuous Foxp3-cre activity reveals a differential requirement for CD28 in Foxp3⁺ and Foxp3⁻ T cells. 2015, 93 (4):417-23 Immunol. Cell Biol.
1440-1711
25533288
10.1038/icb.2014.108
http://hdl.handle.net/10033/600466
Immunology and cell biology
Costimulatory signals by CD28 are critical for thymic regulatory T-cell (Treg) development. To determine the functional relevance of CD28 for peripheral Treg post thymic selection, we crossed the widely used Forkhead box protein 3 (Foxp3)-CreYFP mice to mice bearing a conditional Cd28 allele. Treg-specific CD28 deficiency provoked a severe autoimmune syndrome as a result of a strong disadvantage in competitive fitness and proliferation of CD28-deficient Tregs. By contrast, Treg survival and lineage integrity were not affected by the lack of CD28. This data demonstrate that, even after the initial induction requirement, Treg maintain a higher dependency on CD28 signalling than conventional T cells for homeostasis. In addition, we found the Foxp3-CreYFP allele to be a hypomorph, with reduced Foxp3 protein levels. Furthermore, we report here the stochastic activity of the Foxp3-CreYFP allele in non-Tregs, sufficient to recombine some conditional alleles (including Cd28) but not others (including R26-RFP). This hypomorphism and 'leaky' expression of the Foxp3-CreYFP allele should be considered when analysing the conditionally mutated Treg.
en
Animals
Antigens, CD28
Autoimmunity
Cell Differentiation
Cell Lineage
Cell Survival
Clonal Selection, Antigen-Mediated
Forkhead Transcription Factors
Gene Expression Regulation, Developmental
Homeostasis
Mice
Mice, Transgenic
Signal Transduction
T-Lymphocyte Subsets
T-Lymphocytes, Regulatory
Promiscuous Foxp3-cre activity reveals a differential requirement for CD28 in Foxp3⁺ and Foxp3⁻ T cells.
Article
2018-06-12T21:43:31Z
Costimulatory signals by CD28 are critical for thymic regulatory T-cell (Treg) development. To determine the functional relevance of CD28 for peripheral Treg post thymic selection, we crossed the widely used Forkhead box protein 3 (Foxp3)-CreYFP mice to mice bearing a conditional Cd28 allele. Treg-specific CD28 deficiency provoked a severe autoimmune syndrome as a result of a strong disadvantage in competitive fitness and proliferation of CD28-deficient Tregs. By contrast, Treg survival and lineage integrity were not affected by the lack of CD28. This data demonstrate that, even after the initial induction requirement, Treg maintain a higher dependency on CD28 signalling than conventional T cells for homeostasis. In addition, we found the Foxp3-CreYFP allele to be a hypomorph, with reduced Foxp3 protein levels. Furthermore, we report here the stochastic activity of the Foxp3-CreYFP allele in non-Tregs, sufficient to recombine some conditional alleles (including Cd28) but not others (including R26-RFP). This hypomorphism and 'leaky' expression of the Foxp3-CreYFP allele should be considered when analysing the conditionally mutated Treg.
ORIGINAL
Franckaert et al.pdf
Franckaert et al.pdf
Open Access publication
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2019-08-30 11:37:44.672
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6091262019-08-30T11:25:11Zcom_10033_128109col_10033_128110
Yang, B-H
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Hagemann, S
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Mamareli, P
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Lauer, U
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Hoffmann, U
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Beckstette, M
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Föhse, L
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Prinz, I
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Pezoldt, J
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Suerbaum, S
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Sparwasser, Tim
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http://orcid.org/0000-0001-5645-902X
Hamann, A
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Floess, S
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Huehn, J
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Lochner, M
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Helmholtz Centre for infection research, Inhoffenstr.7, 38124 Braunschweig, Germany.
2016-05-12T09:09:24Z
2016-05-12T09:09:24Z
2016-03
Foxp3(+) T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation. 2016, 9 (2):444-57 Mucosal Immunol
1935-3456
26307665
10.1038/mi.2015.74
http://hdl.handle.net/10033/609126
Mucosal immunology
Foxp3 (forkhead box P3 transcription factor)-expressing regulatory T cells (Tregs) are essential for immunological tolerance, best illustrated by uncontrolled effector T-cell responses and autoimmunity upon loss of Foxp3 expression. Tregs can adopt specific effector phenotypes upon activation, reflecting the diversity of functional demands in the different tissues of the body. Here, we report that Foxp3(+)CD4(+) T cells coexpressing retinoic acid-related orphan receptor-γt (RORγt), the master transcription factor for T helper type 17 (Th17) cells, represent a stable effector Treg lineage. Transcriptomic and epigenetic profiling revealed that Foxp3(+)RORγt(+) T cells display signatures of both Tregs and Th17 cells, although the degree of similarity was higher to Foxp3(+)RORγt(-) Tregs than to Foxp3(-)RORγt(+) T cells. Importantly, Foxp3(+)RORγt(+) T cells were significantly demethylated at Treg-specific epigenetic signature genes such as Foxp3, Ctla-4, Gitr, Eos, and Helios, suggesting that these cells have a stable regulatory rather than inflammatory function. Indeed, adoptive transfer of Foxp3(+)RORγt(+) T cells in the T-cell transfer colitis model confirmed their Treg function and lineage stability in vivo, and revealed an enhanced suppressive capacity as compared with Foxp3(+)RORγt(-) Tregs. Thus, our data suggest that RORγt expression in Tregs contributes to an optimal suppressive capacity during gut-specific immune responses, rendering Foxp3(+)RORγt(+) T cells as an important effector Treg subset in the intestinal system.
en
Foxp3(+) T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation.
Article
2016-09-01T00:00:00Z
Foxp3 (forkhead box P3 transcription factor)-expressing regulatory T cells (Tregs) are essential for immunological tolerance, best illustrated by uncontrolled effector T-cell responses and autoimmunity upon loss of Foxp3 expression. Tregs can adopt specific effector phenotypes upon activation, reflecting the diversity of functional demands in the different tissues of the body. Here, we report that Foxp3(+)CD4(+) T cells coexpressing retinoic acid-related orphan receptor-γt (RORγt), the master transcription factor for T helper type 17 (Th17) cells, represent a stable effector Treg lineage. Transcriptomic and epigenetic profiling revealed that Foxp3(+)RORγt(+) T cells display signatures of both Tregs and Th17 cells, although the degree of similarity was higher to Foxp3(+)RORγt(-) Tregs than to Foxp3(-)RORγt(+) T cells. Importantly, Foxp3(+)RORγt(+) T cells were significantly demethylated at Treg-specific epigenetic signature genes such as Foxp3, Ctla-4, Gitr, Eos, and Helios, suggesting that these cells have a stable regulatory rather than inflammatory function. Indeed, adoptive transfer of Foxp3(+)RORγt(+) T cells in the T-cell transfer colitis model confirmed their Treg function and lineage stability in vivo, and revealed an enhanced suppressive capacity as compared with Foxp3(+)RORγt(-) Tregs. Thus, our data suggest that RORγt expression in Tregs contributes to an optimal suppressive capacity during gut-specific immune responses, rendering Foxp3(+)RORγt(+) T cells as an important effector Treg subset in the intestinal system.
ORIGINAL
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Yang_et_al.pdf
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supplental figures S1-S11 and materials
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10033/609126
oai:hzi.openrepository.com:10033/609126
2019-08-30 11:25:11.152
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6200512019-08-30T11:28:51Zcom_10033_128109col_10033_128110
Goldstein, Jérémie D
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Burlion, Aude
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Zaragoza, Bruno
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Sendeyo, Kélhia
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Polansky, Julia K
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Huehn, Jochen
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Piaggio, Eliane
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Salomon, Benoit L
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Marodon, Gilles
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Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2016-09-13T07:57:50Z
2016-09-13T07:57:50Z
2016
Inhibition of the JAK/STAT Signaling Pathway in Regulatory T Cells Reveals a Very Dynamic Regulation of Foxp3 Expression. 2016, 11 (4):e0153682 PLoS ONE
1932-6203
27077371
10.1371/journal.pone.0153682
http://hdl.handle.net/10033/620051
PloS one
The IL-2/JAK3/STAT-5 signaling pathway is involved on the initiation and maintenance of the transcription factor Foxp3 in regulatory T cells (Treg) and has been associated with demethylation of the intronic Conserved Non Coding Sequence-2 (CNS2). However, the role of the JAK/STAT pathway in controlling Foxp3 in the short term has been poorly investigated. Using two different JAK/STAT pharmacological inhibitors, we observed a detectable loss of Foxp3 after 10 min. of treatment that affected 70% of the cells after one hour. Using cycloheximide, a general inhibitor of mRNA translation, we determined that Foxp3, but not CD25, has a high turnover in IL-2 stimulated Treg. This reduction was correlated with a rapid reduction of Foxp3 mRNA. This loss of Foxp3 was associated with a loss in STAT-5 binding to the CNS2, which however remains demethylated. Consequently, Foxp3 expression returns to normal level upon restoration of basal JAK/STAT signaling in vivo. Reduced expression of several genes defining Treg identity was also observed upon treatment. Thus, our results demonstrate that Foxp3 has a rapid turn over in Treg partly controlled at the transcriptional level by the JAK/STAT pathway.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Animals
DNA Methylation
Forkhead Transcription Factors
Gene Expression Regulation
Humans
Introns
Janus Kinase 3
Mice
Protein Kinase Inhibitors
RNA, Messenger
STAT5 Transcription Factor
Signal Transduction
T-Lymphocytes, Regulatory
Inhibition of the JAK/STAT Signaling Pathway in Regulatory T Cells Reveals a Very Dynamic Regulation of Foxp3 Expression.
Article
2018-06-13T01:10:28Z
The IL-2/JAK3/STAT-5 signaling pathway is involved on the initiation and maintenance of the transcription factor Foxp3 in regulatory T cells (Treg) and has been associated with demethylation of the intronic Conserved Non Coding Sequence-2 (CNS2). However, the role of the JAK/STAT pathway in controlling Foxp3 in the short term has been poorly investigated. Using two different JAK/STAT pharmacological inhibitors, we observed a detectable loss of Foxp3 after 10 min. of treatment that affected 70% of the cells after one hour. Using cycloheximide, a general inhibitor of mRNA translation, we determined that Foxp3, but not CD25, has a high turnover in IL-2 stimulated Treg. This reduction was correlated with a rapid reduction of Foxp3 mRNA. This loss of Foxp3 was associated with a loss in STAT-5 binding to the CNS2, which however remains demethylated. Consequently, Foxp3 expression returns to normal level upon restoration of basal JAK/STAT signaling in vivo. Reduced expression of several genes defining Treg identity was also observed upon treatment. Thus, our results demonstrate that Foxp3 has a rapid turn over in Treg partly controlled at the transcriptional level by the JAK/STAT pathway.
ORIGINAL
Goldstein et al.PDF
Goldstein et al.PDF
Open Access publication
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Erratum.PDF
Erratum.PDF
Erratum to Goldstein et al
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Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6206702019-08-30T11:32:16Zcom_10033_128109col_10033_128110
Uhde, Ann-Kathrin
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Herder, Vanessa
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Akram Khan, Muhammad
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Ciurkiewicz, Malgorzata
ef195e4a3e57f07591376261aabbe6e6
500
Schaudien, Dirk
2037c9ad0461e336af1aebf0799c80e2
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Teich, René
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Floess, Stefan
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Baumgärtner, Wolfgang
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Huehn, Jochen
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Beineke, Andreas
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Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2016-12-15T15:33:36Z
2016-12-15T15:33:36Z
2016
Viral Infection of the Central Nervous System Exacerbates Interleukin-10 Receptor Deficiency-Mediated Colitis in SJL Mice. 2016, 11 (9):e0161883 PLoS ONE
1932-6203
27611574
10.1371/journal.pone.0161883
http://hdl.handle.net/10033/620670
PloS one
Theiler´s murine encephalomyelitis virus (TMEV)-infection is a widely used animal model for studying demyelinating disorders, including multiple sclerosis (MS). The immunosuppressive cytokine Interleukin (IL)-10 counteracts hyperactive immune responses and critically controls immune homeostasis in infectious and autoimmune disorders. In order to investigate the effect of signaling via Interleukin-10 receptor (IL-10R) in infectious neurological diseases, TMEV-infected SJL mice were treated with IL-10R blocking antibody (Ab) in the acute and chronic phase of the disease. The findings demonstrate that (i) Ab-mediated IL-10 neutralization leads to progressive colitis with a reduction in Foxp3+ regulatory T cells and increased numbers of CD8+CD44+ memory T cells as well as activated CD4+CD69+ and CD8+CD69+ T cells in uninfected mice. (ii) Concurrent acute TMEV-infection worsened enteric disease-mediated by IL-10R neutralization. Virus-triggered effects were associated with an enhanced activation of CD4+ T helper cells and CD8+ cytotoxic T lymphocytes and augmented cytokine expression. By contrast, (iii) IL-10R neutralization during chronic TMEV-infection was not associated with enhanced peripheral immunopathology but an increased CD3+ T cell influx in the spinal cord. IL-10R neutralization causes a breakdown in peripheral immune tolerance in genetically predisposed mice, which leads to immune-mediated colitis, resembling inflammatory bowel disease. Hyperactive immune state following IL-10R blockade is enhanced by central nervous system-restricted viral infection in a disease phase-dependent manner.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Viral Infection of the Central Nervous System Exacerbates Interleukin-10 Receptor Deficiency-Mediated Colitis in SJL Mice.
Article
2018-06-13T07:35:27Z
Theiler´s murine encephalomyelitis virus (TMEV)-infection is a widely used animal model for studying demyelinating disorders, including multiple sclerosis (MS). The immunosuppressive cytokine Interleukin (IL)-10 counteracts hyperactive immune responses and critically controls immune homeostasis in infectious and autoimmune disorders. In order to investigate the effect of signaling via Interleukin-10 receptor (IL-10R) in infectious neurological diseases, TMEV-infected SJL mice were treated with IL-10R blocking antibody (Ab) in the acute and chronic phase of the disease. The findings demonstrate that (i) Ab-mediated IL-10 neutralization leads to progressive colitis with a reduction in Foxp3+ regulatory T cells and increased numbers of CD8+CD44+ memory T cells as well as activated CD4+CD69+ and CD8+CD69+ T cells in uninfected mice. (ii) Concurrent acute TMEV-infection worsened enteric disease-mediated by IL-10R neutralization. Virus-triggered effects were associated with an enhanced activation of CD4+ T helper cells and CD8+ cytotoxic T lymphocytes and augmented cytokine expression. By contrast, (iii) IL-10R neutralization during chronic TMEV-infection was not associated with enhanced peripheral immunopathology but an increased CD3+ T cell influx in the spinal cord. IL-10R neutralization causes a breakdown in peripheral immune tolerance in genetically predisposed mice, which leads to immune-mediated colitis, resembling inflammatory bowel disease. Hyperactive immune state following IL-10R blockade is enhanced by central nervous system-restricted viral infection in a disease phase-dependent manner.
ORIGINAL
Uhde et al.PDF
Uhde et al.PDF
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Uhde et al.PDF.txt
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oai:hzi.openrepository.com:10033/620670
2019-08-30 11:32:16.992
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6209582019-08-30T11:26:42Zcom_10033_128109col_10033_128110
Garg, Garima
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Hardtke-Wolenski, Matthias
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Ohkura, Naganari
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Beckstette, Michael
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Miyao, Takahisa
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Geffers, Robert
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http://orcid.org/0000-0003-4409-016X
Floess, Stefan
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Gerdes, Norbert
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Lutgens, Esther
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Osterloh, Anke
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Hori, Shohei
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Sakaguchi, Shimon
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Jaeckel, Elmar
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Huehn, Jochen
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Helmholtz Centre for infection research, Inhoffenstr.7, 38124 Braunschweig, Germany.
2017-06-19T12:24:50Z
2017-06-19T12:24:50Z
2017-05-30
Unique properties of thymic antigen-presenting cells promote epigenetic imprinting of alloantigen-specific regulatory T cells. 2017, 8 (22):35542-35557 Oncotarget
1949-2553
28415767
10.18632/oncotarget.16221
http://hdl.handle.net/10033/620958
Oncotarget
Regulatory T cells (Tregs) are potential immunotherapeutic candidates to induce transplantation tolerance. However, stability of Tregs still remains contentious and may potentially restrict their clinical use. Recent work suggested that epigenetic imprinting of Foxp3 and other Treg-specific signature genes is crucial for stabilization of immunosuppressive properties of Foxp3+ Tregs, and that these events are initiated already during early stages of thymic Treg development. However, the mechanisms governing this process remain largely unknown. Here we demonstrate that thymic antigen-presenting cells (APCs), including thymic dendritic cells (t-DCs) and medullary thymic epithelial cells (mTECs), can induce a more pronounced demethylation of Foxp3 and other Treg-specific epigenetic signature genes in developing Tregs when compared to splenic DCs (sp-DCs). Transcriptomic profiling of APCs revealed differential expression of secreted factors and costimulatory molecules, however neither addition of conditioned media nor interference with costimulatory signals affected Foxp3 induction by thymic APCs in vitro. Importantly, when tested in vivo both mTEC- and t-DC-generated alloantigen-specific Tregs displayed significantly higher efficacy in prolonging skin allograft acceptance when compared to Tregs generated by sp-DCs. Our results draw attention to unique properties of thymic APCs in initiating commitment towards stable and functional Tregs, a finding that could be highly beneficial in clinical immunotherapy.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Unique properties of thymic antigen-presenting cells promote epigenetic imprinting of alloantigen-specific regulatory T cells.
Article
2018-06-12T21:25:10Z
Regulatory T cells (Tregs) are potential immunotherapeutic candidates to induce transplantation tolerance. However, stability of Tregs still remains contentious and may potentially restrict their clinical use. Recent work suggested that epigenetic imprinting of Foxp3 and other Treg-specific signature genes is crucial for stabilization of immunosuppressive properties of Foxp3+ Tregs, and that these events are initiated already during early stages of thymic Treg development. However, the mechanisms governing this process remain largely unknown. Here we demonstrate that thymic antigen-presenting cells (APCs), including thymic dendritic cells (t-DCs) and medullary thymic epithelial cells (mTECs), can induce a more pronounced demethylation of Foxp3 and other Treg-specific epigenetic signature genes in developing Tregs when compared to splenic DCs (sp-DCs). Transcriptomic profiling of APCs revealed differential expression of secreted factors and costimulatory molecules, however neither addition of conditioned media nor interference with costimulatory signals affected Foxp3 induction by thymic APCs in vitro. Importantly, when tested in vivo both mTEC- and t-DC-generated alloantigen-specific Tregs displayed significantly higher efficacy in prolonging skin allograft acceptance when compared to Tregs generated by sp-DCs. Our results draw attention to unique properties of thymic APCs in initiating commitment towards stable and functional Tregs, a finding that could be highly beneficial in clinical immunotherapy.
ORIGINAL
Garg et al.pdf
Garg et al.pdf
Open Access publication
application/pdf
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https://hzi.openrepository.com/bitstream/10033/620958/1/Garg%20et%20al.pdf
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10033/620958
oai:hzi.openrepository.com:10033/620958
2019-08-30 11:26:42.736
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6209782019-08-30T11:36:05Zcom_10033_128109com_10033_620644com_10033_338554col_10033_621787col_10033_128110col_10033_620646
Pasztoi, Maria
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Bonifacius, Agnes
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Pezoldt, Joern
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Kulkarni, Devesha
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Niemz, Jana
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Yang, Juhao
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Teich, René
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Hajek, Janina
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Pisano, Fabio
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Rohde, Manfred
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Dersch, Petra
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Huehn, Jochen
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Helmholtz Centre for infection research, Inhoffenstr.7, 38124 Braunschweig, Germany.
2017-06-23T14:41:00Z
2017-06-23T14:41:00Z
2017-04-04
Yersinia pseudotuberculosis supports Th17 differentiation and limits de novo regulatory T cell induction by directly interfering with T cell receptor signaling. 2017 Cell. Mol. Life Sci.
1420-9071
28378044
10.1007/s00018-017-2516-y
http://hdl.handle.net/10033/620978
Cellular and molecular life sciences : CMLS
Adaptive immunity critically contributes to control acute infection with enteropathogenic Yersinia pseudotuberculosis; however, the role of CD4(+) T cell subsets in establishing infection and allowing pathogen persistence remains elusive. Here, we assessed the modulatory capacity of Y. pseudotuberculosis on CD4(+) T cell differentiation. Using in vivo assays, we report that infection with Y. pseudotuberculosis resulted in enhanced priming of IL-17-producing T cells (Th17 cells), whereas induction of Foxp3(+) regulatory T cells (Tregs) was severely disrupted in gut-draining mesenteric lymph nodes (mLNs), in line with altered frequencies of tolerogenic and proinflammatory dendritic cell (DC) subsets within mLNs. Additionally, by using a DC-free in vitro system, we could demonstrate that Y. pseudotuberculosis can directly modulate T cell receptor (TCR) downstream signaling within naïve CD4(+) T cells and Tregs via injection of effector molecules through the type III secretion system, thereby affecting their functional properties. Importantly, modulation of naïve CD4(+) T cells by Y. pseudotuberculosis resulted in an enhanced Th17 differentiation and decreased induction of Foxp3(+) Tregs in vitro. These findings shed light to the adjustment of the Th17-Treg axis in response to acute Y. pseudotuberculosis infection and highlight the direct modulation of CD4(+) T cell subsets by altering their TCR downstream signaling.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Yersinia pseudotuberculosis supports Th17 differentiation and limits de novo regulatory T cell induction by directly interfering with T cell receptor signaling.
Article
2018-06-12T17:59:47Z
Adaptive immunity critically contributes to control acute infection with enteropathogenic Yersinia pseudotuberculosis; however, the role of CD4(+) T cell subsets in establishing infection and allowing pathogen persistence remains elusive. Here, we assessed the modulatory capacity of Y. pseudotuberculosis on CD4(+) T cell differentiation. Using in vivo assays, we report that infection with Y. pseudotuberculosis resulted in enhanced priming of IL-17-producing T cells (Th17 cells), whereas induction of Foxp3(+) regulatory T cells (Tregs) was severely disrupted in gut-draining mesenteric lymph nodes (mLNs), in line with altered frequencies of tolerogenic and proinflammatory dendritic cell (DC) subsets within mLNs. Additionally, by using a DC-free in vitro system, we could demonstrate that Y. pseudotuberculosis can directly modulate T cell receptor (TCR) downstream signaling within naïve CD4(+) T cells and Tregs via injection of effector molecules through the type III secretion system, thereby affecting their functional properties. Importantly, modulation of naïve CD4(+) T cells by Y. pseudotuberculosis resulted in an enhanced Th17 differentiation and decreased induction of Foxp3(+) Tregs in vitro. These findings shed light to the adjustment of the Th17-Treg axis in response to acute Y. pseudotuberculosis infection and highlight the direct modulation of CD4(+) T cell subsets by altering their TCR downstream signaling.
ORIGINAL
Pasztoi et al.pdf
Pasztoi et al.pdf
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2019-08-30 11:36:05.106
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6210702019-08-30T11:32:17Zcom_10033_128109com_10033_620636col_10033_128110col_10033_620638
Nikolouli, Eirini
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Hardtke-Wolenski, Matthias
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Hapke, Martin
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Beckstette, Michael
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Geffers, Robert
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Floess, Stefan
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Jaeckel, Elmar
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Huehn, Jochen
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Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-08-22T13:53:21Z
2017-08-22T13:53:21Z
2017
Alloantigen-Induced Regulatory T Cells Generated in Presence of Vitamin C Display Enhanced Stability of Foxp3 Expression and Promote Skin Allograft Acceptance. 2017, 8:748 Front Immunol
1664-3224
28702031
10.3389/fimmu.2017.00748
http://hdl.handle.net/10033/621070
Frontiers in immunology
Regulatory T cells (Tregs) are critical for the maintenance of immune homeostasis and self-tolerance and can be therapeutically used for prevention of unwanted immune responses such as allotransplant rejection. Tregs are characterized by expression of the transcription factor Foxp3, and recent work suggests that epigenetic imprinting of Foxp3 and other Treg-specific epigenetic signatures genes is crucial for the stabilization of both Foxp3 expression and immunosuppressive properties within Tregs. Lately, vitamin C was reported to enhance the activity of enzymes of the ten-eleven translocation family, thereby fostering the demethylation of Foxp3 and other Treg-specific epigenetic signatures genes in developing Tregs. Here, we in vitro generated alloantigen-induced Foxp3(+) Tregs (allo-iTregs) in presence of vitamin C. Although vitamin C hardly influenced the transcriptome of allo-iTregs as revealed by RNA-seq, those vitamin C-treated allo-iTregs showed a more pronounced demethylation of Foxp3 and other Treg-specific epigenetic signatures genes accompanied with an enhanced stability of Foxp3 expression. Accordingly, when being tested in vivo in an allogeneic skin transplantation model, vitamin C-treated allo-iTregs showed a superior suppressive capacity. Together, our results pave the way for the establishment of novel protocols for the in vitro generation of alloantigen-induced Foxp3(+) Tregs for therapeutic use in transplantation medicine.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Alloantigen-Induced Regulatory T Cells Generated in Presence of Vitamin C Display Enhanced Stability of Foxp3 Expression and Promote Skin Allograft Acceptance.
Article
2018-06-12T16:43:59Z
Regulatory T cells (Tregs) are critical for the maintenance of immune homeostasis and self-tolerance and can be therapeutically used for prevention of unwanted immune responses such as allotransplant rejection. Tregs are characterized by expression of the transcription factor Foxp3, and recent work suggests that epigenetic imprinting of Foxp3 and other Treg-specific epigenetic signatures genes is crucial for the stabilization of both Foxp3 expression and immunosuppressive properties within Tregs. Lately, vitamin C was reported to enhance the activity of enzymes of the ten-eleven translocation family, thereby fostering the demethylation of Foxp3 and other Treg-specific epigenetic signatures genes in developing Tregs. Here, we in vitro generated alloantigen-induced Foxp3(+) Tregs (allo-iTregs) in presence of vitamin C. Although vitamin C hardly influenced the transcriptome of allo-iTregs as revealed by RNA-seq, those vitamin C-treated allo-iTregs showed a more pronounced demethylation of Foxp3 and other Treg-specific epigenetic signatures genes accompanied with an enhanced stability of Foxp3 expression. Accordingly, when being tested in vivo in an allogeneic skin transplantation model, vitamin C-treated allo-iTregs showed a superior suppressive capacity. Together, our results pave the way for the establishment of novel protocols for the in vitro generation of alloantigen-induced Foxp3(+) Tregs for therapeutic use in transplantation medicine.
ORIGINAL
Nikolouli et al.pdf
Nikolouli et al.pdf
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2019-08-30 11:32:17.068
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6210822019-08-30T11:36:33Zcom_10033_128109com_10033_620591col_10033_128110col_10033_620599
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Helmholtz Centre for infection research GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-08-31T13:10:31Z
2017-08-31T13:10:31Z
2017-08-21
Activated protein C protects from GvHD via PAR2/PAR3 signalling in regulatory T-cells. 2017, 8 (1):311 Nat Commun
2041-1723
28827518
10.1038/s41467-017-00169-4
http://hdl.handle.net/10033/621082
Nature communications
Graft-vs.-host disease (GvHD) is a major complication of allogenic hematopoietic stem-cell(HSC) transplantation. GvHD is associated with loss of endothelial thrombomodulin, but the relevance of this for the adaptive immune response to transplanted HSCs remains unknown. Here we show that the protease-activated protein C (aPC), which is generated by thrombomodulin, ameliorates GvHD aPC restricts allogenic T-cell activation via the protease activated receptor (PAR)2/PAR3 heterodimer on regulatory T-cells (Tregs, CD4(+)FOXP3(+)). Preincubation of pan T-cells with aPC prior to transplantation increases the frequency of Tregs and protects from GvHD. Preincubation of human T-cells (HLA-DR4(-)CD4(+)) with aPC prior to transplantation into humanized (NSG-AB°DR4) mice ameliorates graft-vs.-host disease. The protective effect of aPC on GvHD does not compromise the graft vs. leukaemia effect in two independent tumor cell models. Ex vivo preincubation of T-cells with aPC, aPC-based therapies, or targeting PAR2/PAR3 on T-cells may provide a safe and effective approach to mitigate GvHD.Graft-vs.-host disease is a complication of allogenic hematopoietic stem cell transplantation, and is associated with endothelial dysfunction. Here the authors show that activated protein C signals via PAR2/PAR3 to expand Treg cells, mitigating the disease in mice.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Activated protein C protects from GvHD via PAR2/PAR3 signalling in regulatory T-cells.
Article
2018-06-12T23:27:54Z
Graft-vs.-host disease (GvHD) is a major complication of allogenic hematopoietic stem-cell(HSC) transplantation. GvHD is associated with loss of endothelial thrombomodulin, but the relevance of this for the adaptive immune response to transplanted HSCs remains unknown. Here we show that the protease-activated protein C (aPC), which is generated by thrombomodulin, ameliorates GvHD aPC restricts allogenic T-cell activation via the protease activated receptor (PAR)2/PAR3 heterodimer on regulatory T-cells (Tregs, CD4(+)FOXP3(+)). Preincubation of pan T-cells with aPC prior to transplantation increases the frequency of Tregs and protects from GvHD. Preincubation of human T-cells (HLA-DR4(-)CD4(+)) with aPC prior to transplantation into humanized (NSG-AB°DR4) mice ameliorates graft-vs.-host disease. The protective effect of aPC on GvHD does not compromise the graft vs. leukaemia effect in two independent tumor cell models. Ex vivo preincubation of T-cells with aPC, aPC-based therapies, or targeting PAR2/PAR3 on T-cells may provide a safe and effective approach to mitigate GvHD.Graft-vs.-host disease is a complication of allogenic hematopoietic stem cell transplantation, and is associated with endothelial dysfunction. Here the authors show that activated protein C signals via PAR2/PAR3 to expand Treg cells, mitigating the disease in mice.
ORIGINAL
Rajan et al.pdf
Rajan et al.pdf
Open Access publication
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10033/621082
oai:hzi.openrepository.com:10033/621082
2019-08-30 11:36:33.04
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6210852019-08-30T11:37:00Zcom_10033_128109col_10033_128110
Kyburz, Andreas
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http://orcid.org/0000-0002-1368-8276
Helmholtz Centre for infection research GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-09-01T12:44:31Z
2017-09-01T12:44:31Z
2017-08-12
Helicobacter pylori and its secreted immunomodulator VacA protect against anaphylaxis in experimental models of food allergy. 2017 Clin. Exp. Allergy
1365-2222
28802077
10.1111/cea.12996
http://hdl.handle.net/10033/621085
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology
Food allergy is an increasingly common health problem in Western populations. Epidemiological studies have suggested both positive and negative associations between food allergy and infection with the gastric bacterium Helicobacter pylori.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Helicobacter pylori and its secreted immunomodulator VacA protect against anaphylaxis in experimental models of food allergy.
Article
Food allergy is an increasingly common health problem in Western populations. Epidemiological studies have suggested both positive and negative associations between food allergy and infection with the gastric bacterium Helicobacter pylori.
ORIGINAL
Kyburz_et_al.pdf
Kyburz_et_al.pdf
accepted manuscript
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oai:hzi.openrepository.com:10033/621085
2019-08-30 11:37:00.215
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6211132019-08-30T11:34:22Zcom_10033_128109com_10033_338554col_10033_621787col_10033_128110
Pasztoi, Maria
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Pezoldt, Joern
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Beckstette, Michael
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Lipps, Christoph
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Wirth, Dagmar
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Rohde, M
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http://orcid.org/0000-0003-0522-3580
Paloczi, Krisztina
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Buzas, Edit Iren
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Huehn, Jochen
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Helmholtz Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-09-19T13:06:36Z
2017-09-19T13:06:36Z
2017-08-18
Mesenteric lymph node stromal cell-derived extracellular vesicles contribute to peripheral de novo induction of Foxp3(+) regulatory T cells. 2017 Eur. J. Immunol.
1521-4141
28833065
10.1002/eji.201746960
http://hdl.handle.net/10033/621113
European journal of immunology
Intestinal regulatory T cells (Tregs) are fundamental in peripheral tolerance toward commensals and food-borne antigens. Accordingly, gut-draining mesenteric lymph nodes (mLNs) represent a site of efficient peripheral de novo Treg induction when compared to skin-draining peripheral LNs (pLNs), and we had recently shown that LN stromal cells substantially contribute to this process. Here, we aimed to unravel the underlying molecular mechanisms and generated immortalized fibroblastic reticular cell lines (iFRCs) from mLNs and pLNs, allowing unlimited investigation of this rare stromal cell subset. In line with our previous findings, mLN-iFRCs showed a higher Treg-inducing capacity when compared to pLN-iFRCs. RNA-seq analysis focusing on secreted molecules revealed a more tolerogenic phenotype of mLN- as compared to pLN-iFRCs. Remarkably, mLN-iFRCs produced substantial numbers of microvesicles (MVs) that carried elevated levels of TGF-β when compared to pLN-iFRC-derived MVs, and these novel players of intercellular communication were shown to be responsible for the tolerogenic properties of mLN-iFRCs. Thus, stromal cells originating from mLNs contribute to peripheral tolerance by fostering de novo Treg induction using TGF-β-carrying MVs. This finding provides novel insights into the subcellular/molecular mechanisms of de novo Treg induction and might serve as promising tool for future therapeutic applications to treat inflammatory disorders.
en
info:eu-repo/grantAgreement/EC/H2020/656319
openAccess
http://creativecommons.org/licenses/by-nc-sa/4.0/
Mesenteric lymph node stromal cell-derived extracellular vesicles contribute to peripheral de novo induction of Foxp3(+) regulatory T cells.
Article
2018-06-12T23:48:13Z
Intestinal regulatory T cells (Tregs) are fundamental in peripheral tolerance toward commensals and food-borne antigens. Accordingly, gut-draining mesenteric lymph nodes (mLNs) represent a site of efficient peripheral de novo Treg induction when compared to skin-draining peripheral LNs (pLNs), and we had recently shown that LN stromal cells substantially contribute to this process. Here, we aimed to unravel the underlying molecular mechanisms and generated immortalized fibroblastic reticular cell lines (iFRCs) from mLNs and pLNs, allowing unlimited investigation of this rare stromal cell subset. In line with our previous findings, mLN-iFRCs showed a higher Treg-inducing capacity when compared to pLN-iFRCs. RNA-seq analysis focusing on secreted molecules revealed a more tolerogenic phenotype of mLN- as compared to pLN-iFRCs. Remarkably, mLN-iFRCs produced substantial numbers of microvesicles (MVs) that carried elevated levels of TGF-β when compared to pLN-iFRC-derived MVs, and these novel players of intercellular communication were shown to be responsible for the tolerogenic properties of mLN-iFRCs. Thus, stromal cells originating from mLNs contribute to peripheral tolerance by fostering de novo Treg induction using TGF-β-carrying MVs. This finding provides novel insights into the subcellular/molecular mechanisms of de novo Treg induction and might serve as promising tool for future therapeutic applications to treat inflammatory disorders.
ORIGINAL
Pasztoi et al.pdf
Pasztoi et al.pdf
Open Access article
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2019-08-30 11:34:22.562
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6211192019-08-30T11:36:04Zcom_10033_128109col_10033_128110
Beyer, Marc
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Huehn, Jochen
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Helmholtz Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-09-25T14:09:11Z
2017-09-25T14:09:11Z
2017-01-19
Epigenetic orchestration of thymic Treg cell development. 2017, 18 (2):144-146 Nat. Immunol.
1529-2916
28102221
10.1038/ni.3660
http://hdl.handle.net/10033/621119
Nature immunology
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Epigenetic orchestration of thymic Treg cell development.
Article
2018-01-19T00:00:00Z
ORIGINAL
Beyer &. Huehn.pdf
Beyer &. Huehn.pdf
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Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6211262019-08-30T11:32:17Zcom_10033_620591com_10033_128109com_10033_311308col_10033_620725col_10033_128110col_10033_620721
van Ham, Marco
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Teich, René
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Niemz, Jana
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Amsberg, Nicole
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Wissing, Josef
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Helmholtz-Zetrum für Infektionsforschung GmbH, Inhoffenstr.7, 38124 Braunschweig, Germany.
2017-09-28T12:14:50Z
2017-09-28T12:14:50Z
2017-08-17
TCR signalling network organization at the immunological synapses of murine regulatory T cells. 2017 Eur. J. Immunol.
1521-4141
28833060
10.1002/eji.201747041
http://hdl.handle.net/10033/621126
European journal of immunology
Regulatory T (Treg) cells require T-cell receptor (TCR) signalling to exert their immunosuppressive activity, but the precise organization of the TCR signalling network compared to conventional T (Tconv) cells remains elusive. By using accurate mass spectrometry and multi-epitope ligand cartography (MELC) we characterized TCR signalling and recruitment of TCR signalling components to the immunological synapse (IS) in Treg cells and Tconv cells. With the exception of Themis which we detected in lower amounts in Treg cells, other major TCR signalling components were found equally abundant, however, their phosphorylation-status notably discriminates Treg cells from Tconv cells. Overall, this study identified 121 Treg cell-specific phosphorylations. Short-term triggering of T cell subsets via CD3 and CD28 widely harmonized these variations with the exception of eleven TCR signalling components that mainly regulate cytoskeleton dynamics and molecular transport. Accordingly, conjugation with B cells indeed caused variant cellular morphology and revealed a Treg cell-specific recruitment of TCR signalling components such as PKCθ, PLCγ1 and ZAP70 as well as B cell-derived CD86 into the IS. Together, results from this study support the existence of a Treg cell-specific IS and suggest Treg cell-specific cytoskeleton dynamics as a novel determinant for the unique functional properties of Treg cells.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
TCR signalling network organization at the immunological synapses of murine regulatory T cells.
Article
2018-06-13T21:23:07Z
Regulatory T (Treg) cells require T-cell receptor (TCR) signalling to exert their immunosuppressive activity, but the precise organization of the TCR signalling network compared to conventional T (Tconv) cells remains elusive. By using accurate mass spectrometry and multi-epitope ligand cartography (MELC) we characterized TCR signalling and recruitment of TCR signalling components to the immunological synapse (IS) in Treg cells and Tconv cells. With the exception of Themis which we detected in lower amounts in Treg cells, other major TCR signalling components were found equally abundant, however, their phosphorylation-status notably discriminates Treg cells from Tconv cells. Overall, this study identified 121 Treg cell-specific phosphorylations. Short-term triggering of T cell subsets via CD3 and CD28 widely harmonized these variations with the exception of eleven TCR signalling components that mainly regulate cytoskeleton dynamics and molecular transport. Accordingly, conjugation with B cells indeed caused variant cellular morphology and revealed a Treg cell-specific recruitment of TCR signalling components such as PKCθ, PLCγ1 and ZAP70 as well as B cell-derived CD86 into the IS. Together, results from this study support the existence of a Treg cell-specific IS and suggest Treg cell-specific cytoskeleton dynamics as a novel determinant for the unique functional properties of Treg cells.
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oai:repository.helmholtz-hzi.de:10033/6211612019-08-30T11:28:51Zcom_10033_128109col_10033_128110
Prajeeth, Chittappen K
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Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-11-06T14:31:09Z
2017-11-06T14:31:09Z
2017-10-16
Effectors of Th1 and Th17 cells act on astrocytes and augment their neuroinflammatory properties. 2017, 14 (1):204 J Neuroinflammation
1742-2094
29037246
10.1186/s12974-017-0978-3
http://hdl.handle.net/10033/621161
Journal of neuroinflammation
Autoreactive Th1 and Th17 cells are believed to mediate the pathology of multiple sclerosis in the central nervous system (CNS). Their interaction with microglia and astrocytes in the CNS is crucial for the regulation of the neuroinflammation. Previously, we have shown that only Th1 but not Th17 effectors activate microglia. However, it is not clear which cells are targets of Th17 effectors in the CNS.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Effectors of Th1 and Th17 cells act on astrocytes and augment their neuroinflammatory properties.
Article
2018-06-13T02:42:45Z
Autoreactive Th1 and Th17 cells are believed to mediate the pathology of multiple sclerosis in the central nervous system (CNS). Their interaction with microglia and astrocytes in the CNS is crucial for the regulation of the neuroinflammation. Previously, we have shown that only Th1 but not Th17 effectors activate microglia. However, it is not clear which cells are targets of Th17 effectors in the CNS.
ORIGINAL
Prajeeth et al.pdf
Prajeeth et al.pdf
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hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6211812019-08-30T11:37:00Zcom_10033_128109col_10033_128110
Szilagyi, B A
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Helmholtz-Zentrum für Infektionsforschhung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-11-21T14:18:04Z
2017-11-21T14:18:04Z
2017-11
Gut memories do not fade: epigenetic regulation of lasting gut homing receptor expression in CD4(+) memory T cells. 2017, 10 (6):1443-1454 Mucosal Immunol
1935-3456
28198363
10.1038/mi.2017.7
http://hdl.handle.net/10033/621181
Mucosal immunology
The concept of a "topographical memory" in lymphocytes implies a stable expression of homing receptors mediating trafficking of lymphocytes back to the tissue of initial activation. However, a significant plasticity of the gut-homing receptor α4β7 was found in CD8(+) T cells, questioning the concept. We now demonstrate that α4β7 expression in murine CD4(+) memory T cells is, in contrast, imprinted and remains stable in the absence of the inducing factor retinoic acid (RA) or other stimuli from mucosal environments. Repetitive rounds of RA treatment enhanced the stability of de novo induced α4β7. A novel enhancer element in the murine Itga4 locus was identified that showed, correlating to stability, selective DNA demethylation in mucosa-seeking memory cells and methylation-dependent transcriptional activity in a reporter gene assay. This implies that epigenetic mechanisms contribute to the stabilization of α4β7 expression. Analogous DNA methylation patterns could be observed in the human ITGA4 locus, suggesting that its epigenetic regulation is conserved between mice and men. These data prove that mucosa-specific homing mediated by α4β7 is imprinted in CD4(+) memory T cells, reinstating the validity of the concept of "topographical memory" for mucosal tissues, and imply a critical role of epigenetic mechanisms.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Gut memories do not fade: epigenetic regulation of lasting gut homing receptor expression in CD4(+) memory T cells.
Article
2018-05-01T00:00:00Z
The concept of a "topographical memory" in lymphocytes implies a stable expression of homing receptors mediating trafficking of lymphocytes back to the tissue of initial activation. However, a significant plasticity of the gut-homing receptor α4β7 was found in CD8(+) T cells, questioning the concept. We now demonstrate that α4β7 expression in murine CD4(+) memory T cells is, in contrast, imprinted and remains stable in the absence of the inducing factor retinoic acid (RA) or other stimuli from mucosal environments. Repetitive rounds of RA treatment enhanced the stability of de novo induced α4β7. A novel enhancer element in the murine Itga4 locus was identified that showed, correlating to stability, selective DNA demethylation in mucosa-seeking memory cells and methylation-dependent transcriptional activity in a reporter gene assay. This implies that epigenetic mechanisms contribute to the stabilization of α4β7 expression. Analogous DNA methylation patterns could be observed in the human ITGA4 locus, suggesting that its epigenetic regulation is conserved between mice and men. These data prove that mucosa-specific homing mediated by α4β7 is imprinted in CD4(+) memory T cells, reinstating the validity of the concept of "topographical memory" for mucosal tissues, and imply a critical role of epigenetic mechanisms.
ORIGINAL
Szilagyi et al.pdf
Szilagyi et al.pdf
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oai:hzi.openrepository.com:10033/621181
2019-08-30 11:37:00.017
Helmholtz Zentrum für Infektionsforschung Repository
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oai:repository.helmholtz-hzi.de:10033/6212242019-08-30T11:26:42Zcom_10033_128109com_10033_620644com_10033_620626col_10033_128110col_10033_620646col_10033_620629
Pezoldt, Joern
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http://orcid.org/0000-0001-8177-3280
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr.7, 38124 Braunschweig, Germany.
2018-01-04T10:58:34Z
2018-01-04T10:58:34Z
2017-09-15
Impact of CCR7 on T-Cell Response and Susceptibility to Yersinia pseudotuberculosis Infection. 2017, 216 (6):752-760 J. Infect. Dis.
1537-6613
28329174
10.1093/infdis/jix037
http://hdl.handle.net/10033/621224
The Journal of infectious diseases
To successfully limit pathogen dissemination, an immunological link between the entry tissue of the pathogen and the underlying secondary lymphoid organs (SLOs) needs to be established to prime adaptive immune responses. Here, the prerequisite of CCR7 to mount host immune responses within SLOs during gastrointestinal Yersinia pseudotuberculosis infection to limit pathogen spread was investigated.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Animals
Cell Movement
Dendritic Cells
Genetic Predisposition to Disease
Host-Pathogen Interactions
Intestines
Lymph Nodes
Mice
Myeloid Cells
Peyer's Patches
Receptors, CCR7
Th17 Cells
Yersinia pseudotuberculosis
Yersinia pseudotuberculosis Infections
Impact of CCR7 on T-Cell Response and Susceptibility to Yersinia pseudotuberculosis Infection.
Article
To successfully limit pathogen dissemination, an immunological link between the entry tissue of the pathogen and the underlying secondary lymphoid organs (SLOs) needs to be established to prime adaptive immune responses. Here, the prerequisite of CCR7 to mount host immune responses within SLOs during gastrointestinal Yersinia pseudotuberculosis infection to limit pathogen spread was investigated.
ORIGINAL
Pezoldt et al.pdf
Pezoldt et al.pdf
original manuscript
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Pezoldt et al.pdf.txt
Pezoldt et al.pdf.txt
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oai:hzi.openrepository.com:10033/621224
2019-08-30 11:26:42.797
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6212902019-08-30T11:37:00Zcom_10033_128109col_10033_128110
Schmoeckel, Katrin
aa9be0b510f0ac146f6dbcafaa9bd3fc
500
Mrochen, Daniel M
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500
Hühn, Jochen
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500
Pötschke, Christian
47a9a6efb010d4ecba78782e73c3ea39
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Bröker, Barbara M
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500
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2018-02-21T11:53:15Z
2018-02-21T11:53:15Z
2018
Polymicrobial sepsis and non-specific immunization induce adaptive immunosuppression to a similar degree. 2018, 13 (2):e0192197 PLoS ONE
1932-6203
29415028
10.1371/journal.pone.0192197
http://hdl.handle.net/10033/621290
PloS one
Sepsis is frequently complicated by a state of profound immunosuppression, in its extreme form known as immunoparalysis. We have studied the role of the adaptive immune system in the murine acute peritonitis model. To read out adaptive immunosuppression, we primed post-septic and control animals by immunization with the model antigen TNP-ovalbumin in alum, and measured the specific antibody-responses via ELISA and ELISpot assay as well as T-cell responses in a proliferation assay after restimulation. Specific antibody titers, antibody affinity and plasma cell counts in the bone marrow were reduced in post-septic animals. The antigen-induced splenic proliferation was also impaired. The adaptive immunosuppression was positively correlated with an overwhelming general antibody response to the septic insult. Remarkably, antigen "overload" by non-specific immunization induced a similar degree of adaptive immunosuppression in the absence of sepsis. In both settings, depletion of regulatory T cells before priming reversed some parameters of the immunosuppression. In conclusion, our data show that adaptive immunosuppression occurs independent of profound systemic inflammation and life-threatening illness.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Polymicrobial sepsis and non-specific immunization induce adaptive immunosuppression to a similar degree.
Article
2018-06-13T05:35:47Z
Sepsis is frequently complicated by a state of profound immunosuppression, in its extreme form known as immunoparalysis. We have studied the role of the adaptive immune system in the murine acute peritonitis model. To read out adaptive immunosuppression, we primed post-septic and control animals by immunization with the model antigen TNP-ovalbumin in alum, and measured the specific antibody-responses via ELISA and ELISpot assay as well as T-cell responses in a proliferation assay after restimulation. Specific antibody titers, antibody affinity and plasma cell counts in the bone marrow were reduced in post-septic animals. The antigen-induced splenic proliferation was also impaired. The adaptive immunosuppression was positively correlated with an overwhelming general antibody response to the septic insult. Remarkably, antigen "overload" by non-specific immunization induced a similar degree of adaptive immunosuppression in the absence of sepsis. In both settings, depletion of regulatory T cells before priming reversed some parameters of the immunosuppression. In conclusion, our data show that adaptive immunosuppression occurs independent of profound systemic inflammation and life-threatening illness.
ORIGINAL
Schmoekel et al.pdf
Schmoekel et al.pdf
Open Access publication
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Schmoekel et al.pdf.txt
Schmoekel et al.pdf.txt
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10033/621290
oai:hzi.openrepository.com:10033/621290
2019-08-30 11:37:00.254
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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Sadana, Pooja
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Geyer, Rebecca
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Pezoldt, Joern
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Helmsing, Saskia
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Huehn, Jochen
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http://orcid.org/0000-0001-8071-1379
Hust, Michael
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Dersch, Petra
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Scrima, Andrea
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Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2018-03-23T15:04:02Z
2018-03-23T15:04:02Z
2018-03-13
The invasin D protein fromYersinia pseudotuberculosisselectively binds the Fab region of host antibodies and affects colonization of the intestine. 2018 J. Biol. Chem.
1083-351X
29535184
10.1074/jbc.RA117.001068
http://hdl.handle.net/10033/621332
The Journal of biological chemistry
Yersinia pseudotuberculosis is a Gram-negative bacterium and zoonotic pathogen responsible for a wide range of diseases, ranging from mild diarrhea, enterocolitis, lymphatic adenitis to persistent local inflammation. TheY. pseudotuberculosisinvasin D (InvD) molecule belongs to the invasin (InvA)-type autotransporter proteins, but its structure and function remain unknown. In this study, we present the first crystal structure of InvD, analyzed its expression and function in a murine infection model, and identified its target molecule in the host. We found that InvD is induced at 37°C and expressed in vivo2-4 days after infection, indicating that InvD is a virulence factor. During infection, InvD was expressed in all parts of the intestinal tract, but not in deeper lymphoid tissues. The crystal structure of the C-terminal adhesion domain of InvD revealed a distinct Ig-related fold, that, apart from the canonical β-sheets, comprises various modifications of and insertions into the Ig-core structure. We identified the Fab fragment of host-derived IgG/IgA antibodies as the target of the adhesion domain. Phage display panning and flow cytometry data further revealed that InvD exhibits a preferential binding specificity toward antibodies with VH3/VK1 variable domains and that it is specifically recruited to a subset of B cells. This finding suggests that InvD modulates Ig functions in the intestine and affects direct interactions with a subset of cell surface-exposed B-cell receptors. In summary, our results provide extensive insights into the structure of InvD and its specific interaction with the target molecule in the host.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
The invasin D protein fromYersinia pseudotuberculosisselectively binds the Fab region of host antibodies and affects colonization of the intestine.
Article
Yersinia pseudotuberculosis
is a Gram-negative bacterium and zoonotic pathogen responsible for a wide range of diseases, ranging from mild diarrhea, enterocolitis, lymphatic adenitis to persistent local inflammation. TheY. pseudotuberculosisinvasin D (InvD) molecule belongs to the invasin (InvA)-type autotransporter proteins, but its structure and function remain unknown. In this study, we present the first crystal structure of InvD, analyzed its expression and function in a murine infection model, and identified its target molecule in the host. We found that InvD is induced at 37°C and expressed in vivo2-4 days after infection, indicating that InvD is a virulence factor. During infection, InvD was expressed in all parts of the intestinal tract, but not in deeper lymphoid tissues. The crystal structure of the C-terminal adhesion domain of InvD revealed a distinct Ig-related fold, that, apart from the canonical β-sheets, comprises various modifications of and insertions into the Ig-core structure. We identified the Fab fragment of host-derived IgG/IgA antibodies as the target of the adhesion domain. Phage display panning and flow cytometry data further revealed that InvD exhibits a preferential binding specificity toward antibodies with VH3/VK1 variable domains and that it is specifically recruited to a subset of B cells. This finding suggests that InvD modulates Ig functions in the intestine and affects direct interactions with a subset of cell surface-exposed B-cell receptors. In summary, our results provide extensive insights into the structure of InvD and its specific interaction with the target molecule in the host.
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2019-08-30 11:29:17.633
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6213682019-08-30T11:37:44Zcom_10033_128109col_10033_128110
Uhde, Ann-Kathrin
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Ciurkiewicz, Malgorzata
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Herder, Vanessa
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Khan, Muhammad Akram
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Hensel, Niko
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Claus, Peter
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Beckstette, Michael
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Teich, René
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Floess, Stefan
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Baumgärtner, Wolfgang
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Jung, Klaus
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Huehn, Jochen
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Beineke, Andreas
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Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2018-05-09T12:14:35Z
2018-05-09T12:14:35Z
2018-04-17
Intact interleukin-10 receptor signaling protects from hippocampal damage elicited by experimental neurotropic virus infection of SJL mice. 2018, 8 (1):6106 Sci Rep
2045-2322
29666403
10.1038/s41598-018-24378-z
http://hdl.handle.net/10033/621368
Scientific reports
Theiler's murine encephalomyelitis virus (TMEV) infection represents an experimental mouse model to study hippocampal damage induced by neurotropic viruses. IL-10 is a pleiotropic cytokine with profound anti-inflammatory properties, which critically controls immune homeostasis. In order to analyze IL-10R signaling following virus-induced polioencephalitis, SJL mice were intracerebrally infected with TMEV. RNA-based next generation sequencing revealed an up-regulation of Il10, Il10rα and further genes involved in IL-10 downstream signaling, including Jak1, Socs3 and Stat3 in the brain upon infection. Subsequent antibody-mediated blockade of IL-10R signaling led to enhanced hippocampal damage with neuronal loss and increased recruitment of CD3+ T cells, CD45R+ B cells and an up-regulation of Il1α mRNA. Increased expression of Tgfβ and Foxp3 as well as accumulation of Foxp3+ regulatory T cells and arginase-1+ macrophages/microglia was detected in the hippocampus, representing a potential compensatory mechanism following disturbed IL-10R signaling. Additionally, an increased peripheral Chi3l3 expression was found in spleens of infected mice, which may embody reactive regulatory mechanisms for prevention of excessive immunopathology. The present study highlights the importance of IL-10R signaling for immune regulation and its neuroprotective properties in the context of an acute neurotropic virus infection.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Intact interleukin-10 receptor signaling protects from hippocampal damage elicited by experimental neurotropic virus infection of SJL mice.
Article
2018-06-12T17:17:13Z
Theiler's murine encephalomyelitis virus (TMEV) infection represents an experimental mouse model to study hippocampal damage induced by neurotropic viruses. IL-10 is a pleiotropic cytokine with profound anti-inflammatory properties, which critically controls immune homeostasis. In order to analyze IL-10R signaling following virus-induced polioencephalitis, SJL mice were intracerebrally infected with TMEV. RNA-based next generation sequencing revealed an up-regulation of Il10, Il10rα and further genes involved in IL-10 downstream signaling, including Jak1, Socs3 and Stat3 in the brain upon infection. Subsequent antibody-mediated blockade of IL-10R signaling led to enhanced hippocampal damage with neuronal loss and increased recruitment of CD3+ T cells, CD45R+ B cells and an up-regulation of Il1α mRNA. Increased expression of Tgfβ and Foxp3 as well as accumulation of Foxp3+ regulatory T cells and arginase-1+ macrophages/microglia was detected in the hippocampus, representing a potential compensatory mechanism following disturbed IL-10R signaling. Additionally, an increased peripheral Chi3l3 expression was found in spleens of infected mice, which may embody reactive regulatory mechanisms for prevention of excessive immunopathology. The present study highlights the importance of IL-10R signaling for immune regulation and its neuroprotective properties in the context of an acute neurotropic virus infection.
ORIGINAL
Uhde et al.pdf
Uhde et al.pdf
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Helmholtz Zentrum für Infektionsforschung Repository
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oai:repository.helmholtz-hzi.de:10033/6213752019-08-30T11:36:27Zcom_10033_128109col_10033_128110
Prajeeth, Chittappen K
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Stangel, Martin
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Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2018-05-18T12:51:09Z
2018-05-18T12:51:09Z
2018-02
Regulation of neuroinflammatory properties of glial cells by T cell effector molecules. 2018, 13 (2):234-236 Neural Regen Res
1673-5374
29557369
10.4103/1673-5374.226385
http://hdl.handle.net/10033/621375
Neural regeneration research
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Regulation of neuroinflammatory properties of glial cells by T cell effector molecules.
Article
2018-06-14T09:17:55Z
ORIGINAL
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THUMBNAIL
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oai:hzi.openrepository.com:10033/621375
2019-08-30 11:36:27.718
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6215262019-08-30T11:29:11Zcom_10033_128109col_10033_128110
Prajeeth, Chittappen K
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Kronisch, Julius
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Knier, Benjamin
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Toft-Hansen, Henrik
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Gudi, Viktoria
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Floess, Stefan
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Huehn, Jochen
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Owens, Trevor
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Korn, Thomas
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Stangel, Martin
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HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2018-10-30T15:25:03Z
2018-10-30T15:25:03Z
2017-10-16
1742-2094
29037246
10.1186/s12974-017-0978-3
http://hdl.handle.net/10033/621526
Autoreactive Th1 and Th17 cells are believed to mediate the pathology of multiple sclerosis in the central nervous system (CNS). Their interaction with microglia and astrocytes in the CNS is crucial for the regulation of the neuroinflammation. Previously, we have shown that only Th1 but not Th17 effectors activate microglia. However, it is not clear which cells are targets of Th17 effectors in the CNS. To understand the effects driven by Th17 cells in the CNS, we induced experimental autoimmune encephalomyelitis in wild-type mice and CD4 We observed in α4-deficient mice weak microglial activation but comparable astrogliosis to that of wild-type mice in the regions of the brain populated with Th17 infiltrates, suggesting that Th17 cells target astrocytes and not microglia. In vitro, in response to supernatants from Th1 and Th17 cultures, astrocytes showed altered expression of neurotrophic factors, pro-inflammatory cytokines and chemokines. Furthermore, increased expression of chemokines in Th1- and Th17-treated astrocytes enhanced recruitment of microglia and transendothelial migration of Th17 cells in vitro. Our results demonstrate the delicate interaction between T cell subsets and glial cells and how they communicate to mediate their effects. Effectors of Th1 act on both microglia and astrocytes whereas Th17 effectors preferentially target astrocytes to promote neuroinflammation.
Attribution-NonCommercial-ShareAlike 3.0 United States
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
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Effectors of Th1 and Th17 cells act on astrocytes and augment their neuroinflammatory properties.
Article
Journal of neuroinflammation
2018-10-30T15:25:04Z
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ORIGINAL
Prajeeth et al.pdf
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Open Access publication
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oai:hzi.openrepository.com:10033/621526
2019-08-30 11:29:11.827
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6215332019-08-30T11:29:40Zcom_10033_128109com_10033_620659col_10033_128110col_10033_620660
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Dittrich-Breiholz, Oliver
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Talbot, Steven R
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Robert, Philippe A
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Huehn, Jochen
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Stangel, Martin
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HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany.
2018-11-02T11:50:11Z
2018-11-02T11:50:11Z
2018-01-01
1662-5102
30364000
10.3389/fncel.2018.00352
http://hdl.handle.net/10033/621533
Autoreactive T cells that infiltrate into the central nervous system (CNS) are believed to have a significant role in mediating the pathology of neuroinflammatory diseases like multiple sclerosis. Their interaction with microglia and astrocytes in the CNS is crucial for the regulation of neuroinflammatory processes. Our previous work demonstrated that effectors secreted by Th1 and Th17 cells have different capacities to influence the phenotype and function of glial cells. We have shown that Th1-derived effectors altered the phenotype and function of both microglia and astrocytes whereas Th17-derived effectors induced direct effects only on astrocytes but not on microglia. Here we investigated if effector molecules associated with IFN-γ producing Th1 cells induced different gene expression profiles in microglia and astrocytes. We performed a microarray analysis of RNA isolated from microglia and astrocytes treated with medium and Th-derived culture supernatants and compared the gene expression data. By using the criteria of 2-fold change and a false discovery rate of 0.01 (corrected
Attribution-NonCommercial-ShareAlike 3.0 United States
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Th1 cells
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astrocytes
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cytokines
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interferon-γ
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microglia
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IFN-γ Producing Th1 Cells Induce Different Transcriptional Profiles in Microglia and Astrocytes.
Article
Frontiers in cellular neuroscience
2018-11-02T11:50:12Z
THUMBNAIL
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Prajeeth et al.pdf
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Open Access publication
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10033/621533
oai:hzi.openrepository.com:10033/621533
2019-08-30 11:29:40.87
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6216962019-08-30T11:32:40Zcom_10033_128109col_10033_128110
Garg, Garima
6348f9da6ab69629f89028e3b272ca50
500
Muschaweckh, Andreas
793a2ca55bd5fcea3a4fb45b387c4575
500
Moreno, Helena
454306dcc2b8838beb48e690916df0ea
500
Vasanthakumar, Ajithkumar
092433f677a4e8db262246a8ea3139c5
500
Floess, Stefan
5ffe089d50f6ea39d568657c60ebcc8f
500
Lepennetier, Gildas
c1eb0f9421bcdaba96a8e921c360156b
500
Oellinger, Rupert
831ab6ffe529c41c4830ea5dcd4e7456
500
Zhan, Yifan
3de051548d5842b6d51f60a748056c1d
500
Regen, Tommy
525ff28b4abab7b2375ad8d209c0c57d
500
Hiltensperger, Michael
effa0903e600b4efda706da18e0aead6
500
Peter, Christian
ec088793e2ea664f2a93e50b9355f4f1
500
Aly, Lilian
b54c51507290179146dde62bac503ce9
500
Knier, Benjamin
69385e884f2c76c53cf62c4cb6903039
500
Palam, Lakshmi Reddy
26ea41f202e38481520f9cc707e3ec50
500
Kapur, Reuben
a2296cf45ff53c057e7ffbc2604d5bcc
500
Kaplan, Mark H
ddd44e6ae349ea73e2e3c816d85fe5c1
500
Waisman, Ari
a3d7433c9560189f8f401eb481d01c4c
500
Rad, Roland
7b583a539b5f486c828885c7aec3ecad
500
Schotta, Gunnar
656c32fde694cdb708244dbe7a5fc955
500
Huehn, Jochen
593aa066bacc8199a66ef7fe31379623
600
http://orcid.org/0000-0001-8071-1379
Kallies, Axel
ee8f62eae9956c528e74742569426f35
500
Korn, Thomas
7e79f876e16d70837f9188ee556074b0
500
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2019-02-19T12:39:26Z
2019-02-19T12:39:26Z
2019-02-12
2211-1247
30759395
10.1016/j.celrep.2019.01.070
http://hdl.handle.net/10033/621696
Cell Reports
Summary
Foxp3+ regulatory T (Treg) cells restrict immune pathology in inflamed tissues; however, an inflammatory environment presents a threat to Treg cell identity and function. Here, we establish a transcriptional signature of central nervous system (CNS) Treg cells that accumulate during experimental autoimmune encephalitis (EAE) and identify a pathway that maintains Treg cell function and identity during severe inflammation. This pathway is dependent on the transcriptional regulator Blimp1, which prevents downregulation of Foxp3 expression and “toxic” gain-of-function of Treg cells in the inflamed CNS. Blimp1 negatively regulates IL-6- and STAT3-dependent Dnmt3a expression and function restraining methylation of Treg cell-specific conserved non-coding sequence 2 (CNS2) in the Foxp3 locus. Consequently, CNS2 is heavily methylated when Blimp1 is ablated, leading to a loss of Foxp3 expression and severe disease. These findings identify a Blimp1-dependent pathway that preserves Treg cell stability in inflamed non-lymphoid tissues.
Elsevier (Cell Press)
info:eu-repo/grantAgreement/ERC/CoG 647215
openAccess
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Blimp1
0a4f8fd7-46f7-4dfd-8f65-601af53f6cae
CNS
d1a8cd2b-7ba9-4908-8040-6a7ee5b8e211
CNS2
89eef5d9-ed3f-420a-b056-32494a791318
DNA methyltransferases
b2491385-d6b8-450c-920a-f4649220061d
Foxp3
70610231-c8e5-46db-9b1f-b11618c51fe8
Interleukin-6
2d3cee5c-2cd0-476c-9030-d6a3eade91ca
epigenetic regulation
d10e10ac-357e-4825-8705-86269cd7a488
inflammation
d7ea28a7-3614-4fe2-ad62-4b0288374fe6
regulatory T cells
f2e2e836-d83b-4f67-a7b6-0ecca3b2fa43
Blimp1 Prevents Methylation of Foxp3 and Loss of Regulatory T Cell Identity at Sites of Inflammation.
Article
Cell reports
2019-02-19T12:39:27Z
THUMBNAIL
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MD5
7
false
Table S1.xlsx.jpg
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8
false
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LICENSE
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false
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https://hzi.openrepository.com/bitstream/10033/621696/4/license_rdf
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false
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Document with supplemental information.pdf
Open Access publication with supplementary information
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true
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10033/621696
oai:hzi.openrepository.com:10033/621696
2019-08-30 11:32:40.665
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6217192019-08-30T11:35:12Zcom_10033_128109com_10033_620644col_10033_128110col_10033_620646
Elfiky, Ahmed
de0bea834960ae255a6fba3cf3e76918
500
Bonifacius, Agnes
7388ba497444e1c6681c1b0c117661cc
500
Pezoldt, Joern
12528b25f15cd5d3e26390b9840374ee
500
Pasztoi, Maria
49e798af2f1490d0ff999a34772e8d01
500
Chaoprasid, Paweena
d83523edb72673a7597b94bac0faa8a4
500
Sadana, Pooja
cf193c96d848ddcaa4d23ab201299a43
500
El-Sherbeeny, Nagla
777d53d16365b9a358d8fd84dfa80907
500
Hagras, Magda
6d435e403e953e79af78ffa86f733a75
500
Scrima, Andrea
c3ad854d78113b599fa24cb5e9e6fbcc
500
Dersch, Petra
500f0a5abfe1d165918adfd28d1a4df3
600
http://orcid.org/0000-0001-8177-3280
Huehn, Jochen
593aa066bacc8199a66ef7fe31379623
600
http://orcid.org/0000-0001-8071-1379
HZI, Helmholtz Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig Germany.
2019-03-08T10:27:05Z
2019-03-08T10:27:05Z
2018-12-23
Eur J Microbiol Immunol (Bp). 2018 Nov 28;8(4):101-106. doi:10.1556/1886.2018.00015. eCollection 2018 Dec 23.
2062-509X
30719325
10.1556/1886.2018.00015
http://hdl.handle.net/10033/621719
European Journal of Microbiology and Immunology
Adaptive immunity is essentially required to control acute infection with enteropathogenic
en
Akadémiai Kiadó
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Foxp3
70610231-c8e5-46db-9b1f-b11618c51fe8
500
Yersinia outer proteins
1fc2d9f9-f66f-4958-beb5-066634c49d70
Yersinia pseudotuberculosis
6bfd5c9c-46ef-4da6-b448-343464e7ed1a
cytotoxic necrotizing factor y
8ceea60a-a635-4388-a295-be66a41a6eb3
invasins
8e5cbc44-938b-414a-9694-56cdcf4bd749
regulatory T cells
d4d8234c-79d5-4344-a1ff-8403efdbf011
500
Yersinia Pseudotuberculosis Modulates Regulatory T Cell Stability via Injection of Yersinia Outer Proteins in a Type III Secretion System-Dependent Manner.
Article
European journal of microbiology & immunology
2019-03-08T10:28:53Z
THUMBNAIL
Elfiky et al.pdf.jpg
Elfiky et al.pdf.jpg
Generated Thumbnail
image/jpeg
152963
https://hzi.openrepository.com/bitstream/10033/621719/5/Elfiky%20et%20al.pdf.jpg
04a4198fb780353899d53f081930d1fd
MD5
5
false
TEXT
Elfiky et al.pdf.txt
Elfiky et al.pdf.txt
Extracted text
text/plain
34690
https://hzi.openrepository.com/bitstream/10033/621719/4/Elfiky%20et%20al.pdf.txt
92b87984e9dc6043b16080f92f21fb9b
MD5
4
false
LICENSE
license.txt
license.txt
text/plain
1685
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10033/621719
oai:hzi.openrepository.com:10033/621719
2019-08-30 11:35:12.814
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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Łyszkiewicz, Marcin
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500
Winter, Samantha J
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500
Witzlau, Katrin
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500
Föhse, Lisa
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500
Brownlie, Rebecca
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Puchałka, Jacek
de56cc20d56e08f5615f7e2a7ce70e05
500
Verheyden, Nikita A
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500
Kunze-Schumacher, Heike
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500
Imelmann, Esther
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500
Blume, Jonas
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Raha, Solaiman
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500
Sekiya, Takashi
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Yoshimura, Akihiko
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Frueh, Jochen T
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500
Ullrich, Evelyn
af9077006a4fb510026f464fa5bf64ac
500
Huehn, Jochen
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600
http://orcid.org/0000-0001-8071-1379
Weiss, Siegfried
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500
Gutierrez, Maximiliano G
845fbd98dc2186003588652138d7767f
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Prinz, Immo
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Zamoyska, Rose
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500
Ziętara, Natalia
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Krueger, Andreas
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500
HZI, Helmholtz Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig Germany.
2019-03-28T12:18:39Z
2019-03-28T12:18:39Z
2019-03-01
1545-7885
30856173
10.1371/journal.pbio.2006716
http://hdl.handle.net/10033/621731
PLOS Biology
The interdependence of selective cues during development of regulatory T cells (Treg cells) in the thymus and their suppressive function remains incompletely understood. Here, we analyzed this interdependence by taking advantage of highly dynamic changes in expression of microRNA 181 family members miR-181a-1 and miR-181b-1 (miR-181a/b-1) during late T-cell development with very high levels of expression during thymocyte selection, followed by massive down-regulation in the periphery. Loss of miR-181a/b-1 resulted in inefficient de novo generation of Treg cells in the thymus but simultaneously permitted homeostatic expansion in the periphery in the absence of competition. Modulation of T-cell receptor (TCR) signal strength in vivo indicated that miR-181a/b-1 controlled Treg-cell formation via establishing adequate signaling thresholds. Unexpectedly, miR-181a/b-1-deficient Treg cells displayed elevated suppressive capacity in vivo, in line with elevated levels of cytotoxic T-lymphocyte-associated 4 (CTLA-4) protein, but not mRNA, in thymic and peripheral Treg cells. Therefore, we propose that intrathymic miR-181a/b-1 controls development of Treg cells and imposes a developmental legacy on their peripheral function.
en
PLOS
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
miR-181a/b-1 controls thymic selection of Treg cells and tunes their suppressive capacity.
Article
PLoS biology
2019-03-28T12:50:11Z
CONVERTED2_3541986
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TEXT
Łyszkiewicz et al.pdf.txt
Łyszkiewicz et al.pdf.txt
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LICENSE
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MD5
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ORIGINAL
Łyszkiewicz et al.pdf
Łyszkiewicz et al.pdf
Open Access publication
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MD5
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true
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supplementary figure 1
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supplementary figure 2
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supplementary figure 3
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MD5
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supplementary figure 4
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supplementary figure 5
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MD5
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supplementary figure 6
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pbio.2006716.s007.xlsx
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suulementary table S7
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MD5
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10033/621731
oai:hzi.openrepository.com:10033/621731
2019-08-30 11:33:04.933
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6218632019-07-13T02:26:12Zcom_10033_128109col_10033_128110
Pandiyan, Pushpa
8464e6e3ce449be482ebbdc0371b0c9d
300
Bhaskaran, Natarajan
a6f40ed259cd7a5418f1dd2dbba31ed3
300
Zou, Mangge
2f2d6fdd2ca0a3811e7ae4df7bb99e61
300
Schneider, Elizabeth
36382814f7cae641d6bf94323927c892
300
Jayaraman, Sangeetha
241b1d948ac159a08d828483ef9bc0f1
300
Huehn, Jochen
593aa066bacc8199a66ef7fe31379623
500
http://orcid.org/0000-0001-8071-1379
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2019-07-12T12:22:27Z
2019-07-12T12:22:27Z
2019-01-01
Front Immunol. 2019 Mar 8;10:426. doi: 10.3389/fimmu.2019.00426. eCollection 2019.
1664-3224
30906299
10.3389/fimmu.2019.00426
http://hdl.handle.net/10033/621863
Frontiers in immunology
Mammals co-exist with resident microbial ecosystem that is composed of an incredible number and diversity of bacteria, viruses and fungi. Owing to direct contact between resident microbes and mucosal surfaces, both parties are in continuous and complex interactions resulting in important functional consequences. These interactions govern immune homeostasis, host response to infection, vaccination and cancer, as well as predisposition to metabolic, inflammatory and neurological disorders. Here, we discuss recent studies on direct and indirect effects of resident microbiota on regulatory T cells (Tregs) and Th17 cells at the cellular and molecular level. We review mechanisms by which commensal microbes influence mucosa in the context of bioactive molecules derived from resident bacteria, immune senescence, chronic inflammation and cancer. Lastly, we discuss potential therapeutic applications of microbiota alterations and microbial derivatives, for improving resilience of mucosal immunity and combating immunopathology.
en
Frontiers
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Th17
Treg
antibiotics
inflammation
microbiome
mucosa
mucosal immunity
resident microbes
Microbiome Dependent Regulation of T and Th17 Cells in Mucosa.
Article
Frontiers in immunology
2019-07-12T12:22:27Z
THUMBNAIL
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MD5
5
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Pandiya et al.pdf.txt
Pandiya et al.pdf.txt
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https://hzi.openrepository.com/bitstream/10033/621863/4/Pandiya%20et%20al.pdf.txt
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LICENSE
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Pandiya et al.pdf
Pandiya et al.pdf
Open Access publication
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MD5
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true
10033/621863
oai:hzi.openrepository.com:10033/621863
2019-07-13 02:26:12.754
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6218742019-08-30T11:26:40Zcom_10033_128109col_10033_128110
Pandiyan, Pushpa
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500
Bhaskaran, Natarajan
aa3c9aa7dd70223bd5d101b8bb175bd4
500
Zou, Mangge
de8474b672902c8ee0bb1574c2b7d1ed
500
Schneider, Elizabeth
8ba4eea50dcde3a654d9c3d3c570ffb9
500
Jayaraman, Sangeetha
ac8e2aad54fd2f211a8832032abb6c2d
500
Huehn, Jochen
593aa066bacc8199a66ef7fe31379623
600
http://orcid.org/0000-0001-8071-1379
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2019-07-15T09:51:16Z
2019-07-15T09:51:16Z
2019-01-01
Front Immunol. 2019 Mar 8;10:426. doi: 10.3389/fimmu.2019.00426. eCollection 2019.
1664-3224
30906299
10.3389/fimmu.2019.00426
http://hdl.handle.net/10033/621874
Frontiers in immunology
Mammals co-exist with resident microbial ecosystem that is composed of an incredible number and diversity of bacteria, viruses and fungi. Owing to direct contact between resident microbes and mucosal surfaces, both parties are in continuous and complex interactions resulting in important functional consequences. These interactions govern immune homeostasis, host response to infection, vaccination and cancer, as well as predisposition to metabolic, inflammatory and neurological disorders. Here, we discuss recent studies on direct and indirect effects of resident microbiota on regulatory T cells (Tregs) and Th17 cells at the cellular and molecular level. We review mechanisms by which commensal microbes influence mucosa in the context of bioactive molecules derived from resident bacteria, immune senescence, chronic inflammation and cancer. Lastly, we discuss potential therapeutic applications of microbiota alterations and microbial derivatives, for improving resilience of mucosal immunity and combating immunopathology.
en
Frontiers
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Th17
Treg
antibiotics
inflammation
microbiome
mucosa
mucosal immunity
resident microbes
Microbiome Dependent Regulation of Tregs and Th17 Cells in Mucosa.
Article
Frontiers in immunology
2019-07-15T09:51:16Z
THUMBNAIL
Pandiyan et al.pdf.jpg
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ORIGINAL
Pandiyan et al.pdf
Pandiyan et al.pdf
Open Access publication
application/pdf
2864158
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oai:hzi.openrepository.com:10033/621874
2019-08-30 11:26:40.545
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6219112019-08-30T11:26:41Zcom_10033_128109col_10033_621829col_10033_128110
Schuster, Marc
83bc13ce366f7027f136008c4cc5bd00
500
Plaza-Sirvent, Carlos
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500
Visekruna, Alexander
aa02679a13c0946aadb49a31edc53dca
600
http://orcid.org/0000-0002-5207-9545
Huehn, Jochen
81855dd40035a02edad8ee83ce210282
500
Schmitz, Ingo
d064a965762a0bd3539b3090354dba25
600
http://orcid.org/0000-0002-5360-0419
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2019-08-20T13:39:56Z
2019-08-20T13:39:56Z
2019-01-01
1664-3224
31354726
10.3389/fimmu.2019.01583
http://hdl.handle.net/10033/621911
Frontiers in Immunology
Next to the classical developmental route, in which first CD25 and subsequently Foxp3 are induced to generate thymic regulatory T (Treg) cells, an alternative route has been described. This alternative route is characterized by reciprocal induction of Foxp3 and CD25, with CD25 induction being required to rescue developing Treg cells from Foxp3-induced apoptosis. NF-κB has been demonstrated to be crucial for the development of thymic Treg cells via the classical route. However, its impact on the alternative route is poorly characterized. Using single and double deficient mice for key regulators of the classical route, c-Rel and IκBNS, we here demonstrate that NF-κB is essential for the generation of alternative CD25-Foxp3+ precursors, as well. Thus, c-Rel and IκBNS govern both routes of thymic Treg cell development.
en
Frontiers
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
NF-κB
cell differentiation
common γ-chain cytokines
regulatory T cell
thymus
transcription factor
Generation of Foxp3CD25 Regulatory T-Cell Precursors Requires c-Rel and IκB.
Article
Frontiers in immunology
2019-08-20T13:39:57Z
THUMBNAIL
Schuster et al.pdf.jpg
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Generated Thumbnail
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Schuster et al.pdf.txt
Schuster et al.pdf.txt
Extracted text
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LICENSE
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CC-LICENSE
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Schuster et al.pdf
Schuster et al.pdf
OPen Access publication
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oai:hzi.openrepository.com:10033/621911
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Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6220092019-11-08T02:20:50Zcom_10033_128109col_10033_128110
Cossarizza, Andrea
5d0c7d24d7bae9d2610083a7d3c37d6b
300
Chang, Hyun-Dong
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300
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8c744731e506bea55e4564df47f3794d
300
Adam, Dieter
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Adam-Klages, Sabine
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300
Agace, William W
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300
Aghaeepour, Nima
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300
Akdis, Mübeccel
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300
Allez, Matthieu
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300
Almeida, Larissa Nogueira
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300
Alvisi, Giorgia
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300
Anderson, Graham
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300
Andrä, Immanuel
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Annunziato, Francesco
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Eur J Immunol. 2019 Oct;49(10):1457-1973. doi: 10.1002/eji.201970107.
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These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion.
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Attribution-NonCommercial-ShareAlike 4.0 International
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Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition).
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Herppich, Susanne
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300
Toker, Aras
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500
Pietzsch, Beate
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500
Kitagawa, Yohko
06d5534e5859acc346f381efc7bffc20
300
Ohkura, Naganari
9bec8c46de038f72c88ce107cc6a263f
500
Miyao, Takahisa
9efc8934b73905f52793f39dc8c9b8e4
500
Floess, Stefan
5ffe089d50f6ea39d568657c60ebcc8f
500
Hori, Shohei
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500
Sakaguchi, Shimon
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Huehn, Jochen
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HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2019-11-26T14:32:23Z
2019-11-26T14:32:23Z
2019-01-01
Front Immunol. 2019 Oct 11;10:2382. doi: 10.3389/fimmu.2019.02382. eCollection 2019.
1664-3224
31681278
10.3389/fimmu.2019.02382
http://hdl.handle.net/10033/622031
Frontiers in Immunology
Regulatory T (Treg) cells mainly develop within the thymus and arise from CD25+Foxp3- (CD25+ TregP) or CD25-Foxp3+ (Foxp3+ TregP) Treg cell precursors resulting in Treg cells harboring distinct transcriptomic profiles and complementary T cell receptor repertoires. The stable and long-term expression of Foxp3 in Treg cells and their stable suppressive phenotype are controlled by the demethylation of Treg cell-specific epigenetic signature genes including an evolutionarily conserved CpG-rich element within the Foxp3 locus, the Treg-specific demethylated region (TSDR). Here we analyzed the dynamics of the imprinting of the Treg cell-specific epigenetic signature genes in thymic Treg cells. We could demonstrate that CD25+Foxp3+ Treg cells show a progressive demethylation of most signature genes during maturation within the thymus. Interestingly, a partial demethylation of several Treg cell-specific epigenetic signature genes was already observed in Foxp3+ TregP but not in CD25+ TregP. Furthermore, Foxp3+ TregP were very transient in nature and arose at a more mature developmental stage when compared to CD25+ TregP. When the two Treg cell precursors were cultured in presence of IL-2, a factor known to be critical for thymic Treg cell development, we observed a major impact of IL-2 on the demethylation of the TSDR with a more pronounced effect on Foxp3+ TregP. Together, these results suggest that the establishment of the Treg cell-specific hypomethylation pattern is a continuous process throughout thymic Treg cell development and that the two known Treg cell precursors display distinct dynamics for the imprinting of the Treg cell-specific epigenetic signature genes.
en
Frontiers
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Foxp3
IL-2
TSDR
Treg cell
Treg cell precursors
demethylation
epigenetic signature
thymus
Dynamic Imprinting of the Treg Cell-Specific Epigenetic Signature in Developing Thymic Regulatory T Cells.
Article
Frontiers in immunology
2019-11-26T14:32:23Z
THUMBNAIL
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Open Access publication
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10033/622031
oai:repository.helmholtz-hzi.de:10033/622031
2019-11-27 02:00:58.868
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6220742020-01-11T02:14:02Zcom_10033_128109col_10033_128110
Andersen, Liisa
b060cbd7ec41330e1ba302686929feac
300
Gülich, Alexandra Franziska
e9f4819b3a65c378c8a545c2ae3b8540
300
Alteneder, Marlis
01bc7d8f8ae7933045c31e1c1dfee6a2
300
Preglej, Teresa
1bd74e0eb03ac4f14ee02116f9ae5a9f
300
Orola, Maria Jonah
51476720e0dc482998a112ffcd2f4b58
300
Dhele, Narendra
624c87f525a9757bd9b9622ded77142f
300
Stolz, Valentina
9532fc5263a21a1f3bb3047b8dc95703
300
Schebesta, Alexandra
5d1ebd1fa242010d9e596c26f5b5a081
300
Hamminger, Patricia
a22197e3ca40a7e3aaedcb408c6b7fd0
300
Hladik, Anastasiya
5da2ecb47cc60487f08fd0f28734574d
500
Floess, Stefan
5ffe089d50f6ea39d568657c60ebcc8f
500
Krausgruber, Thomas
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300
Faux, Thomas
0b8d4026085310f845bee8b9827dc524
300
Andrabi, Syed Bilal Ahmad
67737a48ac1e9c15c38826dbb2504f58
300
Huehn, Jochen
593aa066bacc8199a66ef7fe31379623
600
http://orcid.org/0000-0001-8071-1379
Knapp, Sylvia
246e25c24804ddd6fee794df7bff0739
500
Sparwasser, Tim
b9a321f14389c2eaffa0abc915b958bf
500
Bock, Christoph
56953e3d4178944a9d2934bb5a7f2db8
500
Laiho, Asta
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300
Elo, Laura L
7a74db1a8d82bd265b0ca74dc35c3d5e
300
Rasool, Omid
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300
Lahesmaa, Riitta
5fea317d03c25e4519f3bf7390422901
300
Sakaguchi, Shinya
124bba0a50de0fc500b6030a7f6797cd
300
Ellmeier, Wilfried
7ef26f9f963228ea32b0633014354a8a
300
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2020-01-10T14:46:16Z
2020-01-10T14:46:16Z
2019-12-24
Cell Rep. 2019 Dec 24;29(13):4447-4459.e6. doi: 10.1016/j.celrep.2019.11.089.
2211-1247
31875552
10.1016/j.celrep.2019.11.089
http://hdl.handle.net/10033/622074
Cell Reports
Forkhead box protein P3+ (FOXP3+) regulatory T cells (Treg cells) play a key role in maintaining tolerance and immune homeostasis. Here, we report that a T cell-specific deletion of the transcription factor MAZR (also known as PATZ1) leads to an increased frequency of Treg cells, while enforced MAZR expression impairs Treg cell differentiation. Further, MAZR expression levels are progressively downregulated during thymic Treg cell development and during in-vitro-induced human Treg cell differentiation, suggesting that MAZR protein levels are critical for controlling Treg cell development. However, MAZR-deficient Treg cells show only minor transcriptional changes ex vivo, indicating that MAZR is not essential for establishing the transcriptional program of peripheral Treg cells. Finally, the loss of MAZR reduces the clinical score in dextran-sodium sulfate (DSS)-induced colitis, suggesting that MAZR activity in T cells controls the extent of intestinal inflammation. Together, these data indicate that MAZR is part of a Treg cell-intrinsic transcriptional network that modulates Treg cell development.
en
Elsevier/ Cel Press
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
DSS-induced colitis
FOXP3
MAZR
PATZ1
T(reg)
regulatory T cells
The Transcription Factor MAZR/PATZ1 Regulates the Development of FOXP3 Regulatory T Cells.
Article
Cell reports
2020-01-10T14:46:16Z
THUMBNAIL
Andersen et al.pdf.jpg
Andersen et al.pdf.jpg
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Andersen et al.pdf.txt
Andersen et al.pdf.txt
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10033/622074
oai:repository.helmholtz-hzi.de:10033/622074
2020-01-11 02:14:02.524
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6221012020-01-22T02:27:15Zcom_10033_128109com_10033_620636col_10033_128110col_10033_620638
Maluski, Marcel
a9a86c7bfc979a59d52b8dc701d7a621
300
Ghosh, Arnab
a4c4187211f17adf7d2af99c1fca909d
300
Herbst, Jessica
b19f716b857b91bb4e296462ff4f1111
300
Scholl, Vanessa
a36b1bf1a5de05a90e48061b273e5ed5
300
Baumann, Rolf
e4de98755a495364f53a4f2be97edb58
300
Huehn, Jochen
81855dd40035a02edad8ee83ce210282
500
Geffers, Robert
9b3bb6a9df0a5d94975176f31cbd0bf7
500
Meyer, Johann
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500
Maul, Holger
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300
Eiz-Vesper, Britta
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500
Krueger, Andreas
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500
Schambach, Axel
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500
van den Brink, Marcel Rm
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300
Sauer, Martin G
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HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2020-01-21T14:09:11Z
2020-01-21T14:09:11Z
2019-12-02
J Clin Invest. 2019 Dec 2;129(12):5108-5122. doi: 10.1172/JCI126350.
1558-8238
31479431
10.1172/JCI126350
http://hdl.handle.net/10033/622101
The Journal of clinical investigation
The transcription factor B cell CLL/lymphoma 11B (BCL11B) is indispensable for T lineage development of lymphoid progenitors. Here, we show that chimeric antigen receptor (CAR) expression during early phases of ex vivo generation of lymphoid progenitors suppressed BCL11B, leading to suppression of T cell-associated gene expression and acquisition of NK cell-like properties. Upon adoptive transfer into hematopoietic stem cell transplant recipients, CAR-expressing lymphoid progenitors differentiated into CAR-induced killer (CARiK) cells that mediated potent antigen-directed antileukemic activity even across MHC barriers. CD28 and active immunoreceptor tyrosine-based activation motifs were critical for a functional CARiK phenotype. These results give important insights into differentiation of murine and human lymphoid progenitors driven by synthetic CAR transgene expression and encourage further evaluation of ex vivo-generated CARiK cells for targeted immunotherapy.
en
American Society for Clinical Investigation
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Immunology
Immunotherapy
Leukemias
T cell development
Transplantation
Chimeric antigen receptor-induced BCL11B suppression propagates NK-like cell development.
Article
The Journal of clinical investigation
2020-01-21T14:09:11Z
THUMBNAIL
Maluski et al.pdf.jpg
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Generated Thumbnail
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Maluski et al.pdf.txt
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LICENSE
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oai:repository.helmholtz-hzi.de:10033/622101
2020-01-22 02:27:15.02
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6221482020-02-20T02:04:23Zcom_10033_128109col_10033_128110
Nikolouli, Eirini
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Feuerer, Markus
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Huehn, Jochen
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http://orcid.org/0000-0001-8071-1379
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2020-02-19T11:53:05Z
2020-02-19T11:53:05Z
2020-01-27
Cell Mol Immunol. 2020 Jan 27. pii: 10.1038/s41423-019-0352-8. doi: 10.1038/s41423-019-0352-8.
2042-0226
31988493
10.1038/s41423-019-0352-8
http://hdl.handle.net/10033/622148
Cellular and molecular Immunology
The vast majority of Foxp3+ regulatory T cells (Tregs) are generated in the thymus, and several factors, such as cytokines and unique thymic antigen-presenting cells, are known to contribute to the development of these thymus-derived Tregs (tTregs). Here, we report the existence of a specific subset of Foxp3+ Tregs within the thymus that is characterized by the expression of IL-1R2, which is a decoy receptor for the inflammatory cytokine IL-1. Detailed flow cytometric analysis of the thymocytes from Foxp3hCD2xRAG1GFP reporter mice revealed that the IL-1R2+ Tregs are mainly RAG1GFP- and CCR6+CCR7-, demonstrating that these Tregs are recirculating cells entering the thymus from the periphery and that they have an activated phenotype. In the spleen, the majority of IL-1R2+ Tregs express neuropilin-1 (Nrp-1) and Helios, suggesting a thymic origin for these Tregs. Interestingly, among all tissues studied, the highest frequency of IL-1R2+ Tregs was observed in the thymus, indicating preferential recruitment of this Treg subset by the thymus. Using fetal thymic organ cultures (FTOCs), we demonstrated that increased concentrations of exogenous IL-1β blocked intrathymic Treg development, resulting in a decreased frequency of CD25+Foxp3+ tTregs and an accumulation of CD25+Foxp3- Treg precursors. Interestingly, the addition of IL-1R2+ Tregs, but not IL-1R2- Tregs, to reaggregated thymic organ cultures (RTOCs) abrogated the IL-1β-mediated blockade, demonstrating that these recirculating IL-1R2+ Tregs can quench IL-1 signaling in the thymus and thereby maintain thymic Treg development even under inflammatory conditions.
en
Springer Nature
info:eu-repo/grantAgreement/EC/H2020/648145
embargoedAccess
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
IL-1 system
Inflammation
Thymus
Treg development
Recirculating IL-1R2 Tregs fine-tune intrathymic Treg development under inflammatory conditions.
Article
Cellular & molecular immunology
THUMBNAIL
2020-07-27
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oai:repository.helmholtz-hzi.de:10033/622148
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Helmholtz Zentrum für Infektionsforschung Repository
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oai:repository.helmholtz-hzi.de:10033/6221862020-03-11T02:09:21Zcom_10033_128109col_10033_128110
Andersen, Liisa
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Andrabi, Syed Bilal Ahmad
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Huehn, Jochen
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http://orcid.org/0000-0001-8071-1379
Knapp, Sylvia
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500
Sparwasser, Tim
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500
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Laiho, Asta
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Elo, Laura L
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Lahesmaa, Riitta
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HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2020-03-03T14:53:08Z
2020-03-03T14:53:08Z
2019-12-24
Cell Rep. 2019 Dec 24;29(13):4447-4459.e6. doi: 10.1016/j.celrep.2019.11.089.
2211-1247
31875552
10.1016/j.celrep.2019.11.089
http://hdl.handle.net/10033/622186
Cell reports
Forkhead box protein P3+ (FOXP3+) regulatory T cells (Treg cells) play a key role in maintaining tolerance and immune homeostasis. Here, we report that a T cell-specific deletion of the transcription factor MAZR (also known as PATZ1) leads to an increased frequency of Treg cells, while enforced MAZR expression impairs Treg cell differentiation. Further, MAZR expression levels are progressively downregulated during thymic Treg cell development and during in-vitro-induced human Treg cell differentiation, suggesting that MAZR protein levels are critical for controlling Treg cell development. However, MAZR-deficient Treg cells show only minor transcriptional changes ex vivo, indicating that MAZR is not essential for establishing the transcriptional program of peripheral Treg cells. Finally, the loss of MAZR reduces the clinical score in dextran-sodium sulfate (DSS)-induced colitis, suggesting that MAZR activity in T cells controls the extent of intestinal inflammation. Together, these data indicate that MAZR is part of a Treg cell-intrinsic transcriptional network that modulates Treg cell development.
en
Elsevier/Cell Press
info:eu-repo/grantAgreement/EC/H2020/677943
openAccess
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
DSS-induced colitis
FOXP3
MAZR
PATZ1
T(reg)
regulatory T cells
The Transcription Factor MAZR/PATZ1 Regulates the Development of FOXP3 Regulatory T Cells.
Article
Cell reports
2020-03-03T14:53:09Z
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Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6222562020-05-13T01:29:17Zcom_10033_128109col_10033_128110
Kouakanou, Léonce
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Peters, Christian
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Sun, Qiwei
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Floess, Stefan
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Bhat, Jaydeep
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Huehn, Jochen
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Kabelitz, Dieter
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HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2020-05-12T09:06:17Z
2020-05-12T09:06:17Z
2020-04-16
Sci Rep. 2020 Apr 16;10(1):6550. doi: 10.1038/s41598-020-63572-w.
32300237
10.1038/s41598-020-63572-w
http://hdl.handle.net/10033/622256
2045-2322
Scientific reports
Human γδ T cells are potent cytotoxic effector cells, produce a variety of cytokines, and can acquire regulatory activity. Induction of FOXP3, the key transcription factor of regulatory T cells (Treg), by TGF-β in human Vγ9 Vδ2 T cells has been previously reported. Vitamin C is an antioxidant and acts as multiplier of DNA hydroxymethylation. Here we have investigated the effect of the more stable phospho-modified Vitamin C (pVC) on TGF-β-induced FOXP3 expression and the resulting regulatory activity of highly purified human Vγ9 Vδ2 T cells. pVC significantly increased the TGF-β-induced FOXP3 expression and stability and also increased the suppressive activity of Vγ9 Vδ2 T cells. Importantly, pVC induced hypomethylation of the Treg-specific demethylated region (TSDR) in the FOXP3 gene. Genome-wide methylation analysis by Reduced Representation Bisulfite Sequencing additionally revealed differentially methylated regions in several important genes upon pVC treatment of γδ T cells. While Vitamin C also enhances effector functions of Vγ9 Vδ2 T cells in the absence of TGF-β, our results demonstrate that pVC potently increases the suppressive activity and FOXP3 expression in TGF-β-treated Vγ9 Vδ2 T cells by epigenetic modification of the FOXP3 gene
en
Nature Publishing Group
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Vitamin C supports conversion of human γδ T cells into FOXP3-expressing regulatory cells by epigenetic regulation.
Article
10
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6550
Scientific reports
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2020-05-12T09:06:18Z
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10033/622256
oai:repository.helmholtz-hzi.de:10033/622256
2020-05-13 01:29:17.704
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6223052020-06-23T03:31:11Zcom_10033_128109col_10033_128110
Kyburz, Andreas
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500
Fallegger, Angela
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300
Zhang, Xiaozhou
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Altobelli, Aleksandra
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Artola-Boran, Mariela
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Borbet, Timothy
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300
Urban, Sabine
d9bdfbfe0ba947f3bb3dc4a6b5a65440
500
Paul, Petra
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Münz, Christian
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500
Floess, Stefan
5ffe089d50f6ea39d568657c60ebcc8f
500
Huehn, Jochen
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600
http://orcid.org/0000-0001-8071-1379
Cover, Timothy L
5123487a087a6003142d9f4944acfa38
500
Blaser, Martin J
30c15c589707b5c7480f2002737fd565
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Taube, Christian
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Müller, Anne
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http://orcid.org/0000-0002-1368-8276
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2020-06-22T09:50:53Z
2020-06-22T09:50:53Z
2018-09-19
J Allergy Clin Immunol. 2019;143(4):1496-1512.e11. doi:10.1016/j.jaci.2018.07.046.
30240703
10.1016/j.jaci.2018.07.046
http://hdl.handle.net/10033/622305
1097-6825
The Journal of allergy and clinical immunology
PMC6592617
Background: Transmaternal exposure to tobacco, microbes, nutrients, and other environmental factors shapes the fetal immune system through epigenetic processes. The gastric microbe Helicobacter pylori represents an ancestral constituent of the human microbiota that causes gastric disorders on the one hand and is inversely associated with allergies and chronic inflammatory conditions on the other.
Objective: Here we investigate the consequences of transmaternal exposure to H pylori in utero and/or during lactation for susceptibility to viral and bacterial infection, predisposition to allergic airway inflammation, and development of immune cell populations in the lungs and lymphoid organs.
Methods: We use experimental models of house dust mite- or ovalbumin-induced airway inflammation and influenza A virus or Citrobacter rodentium infection along with metagenomics analyses, multicolor flow cytometry, and bisulfite pyrosequencing, to study the effects of H pylori on allergy severity and immunologic and microbiome correlates thereof.
Results: Perinatal exposure to H pylori extract or its immunomodulator vacuolating cytotoxin confers robust protective effects against allergic airway inflammation not only in first- but also second-generation offspring but does not increase susceptibility to viral or bacterial infection. Immune correlates of allergy protection include skewing of regulatory over effector T cells, expansion of regulatory T-cell subsets expressing CXCR3 or retinoic acid-related orphan receptor γt, and demethylation of the forkhead box P3 (FOXP3) locus. The composition and diversity of the gastrointestinal microbiota is measurably affected by perinatal H pylori exposure.
Conclusion: We conclude that exposure to H pylori has consequences not only for the carrier but also for subsequent generations that can be exploited for interventional purposes.
Keywords: Allergic airway inflammation; epigenetic regulation of allergy and asthma; immune regulation; immune tolerance; metagenomics; microbial interventions during pregnancy.
en
Elsevier
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592617/
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Allergic airway inflammation
epigenetic regulation of allergy and asthma
immune regulation
immune tolerance
metagenomics
microbial interventions during pregnancy
Transmaternal Helicobacter pylori exposure reduces allergic airway inflammation in offspring through regulatory T cells.
Article
Other
143
4
1496
1512.e11
The Journal of allergy and clinical immunology
United States
United States
United States
United States
United States
United States
2020-06-22T09:50:55Z
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10033/622305
oai:repository.helmholtz-hzi.de:10033/622305
2020-06-23 03:31:11.173
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6223142020-06-26T02:39:29Zcom_10033_128109col_10033_128110
Matthias, Julia
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Zeiträg, Julia
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Kolz, Anna
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Chao, Ying-Yin
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Soll, Dominik
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de Almeida, Gustavo P
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Glasmacher, Elke
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Jacobsen, Ilse D
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Riedel, Thomas
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Peters, Anneli
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Floess, Stefan
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Huehn, Jochen
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Baumjohann, Dirk
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Huber, Magdalena
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Korn, Thomas
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Zielinski, Christina E
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HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2020-06-25T14:18:44Z
2020-06-25T14:18:44Z
2020-06-02
J Clin Invest. 2020;137786. doi:10.1172/JCI137786.
32484796
10.1172/JCI137786
http://hdl.handle.net/10033/622314
1558-8238
The Journal of clinical investigation
T helper cells integrate signals from their microenvironment to acquire distinct specialization programs for efficient clearance of diverse pathogens or for immunotolerance. Ionic signals have recently been demonstrated to affect T cell polarization and function. Sodium chloride (NaCl) was proposed to accumulate in peripheral tissues upon dietary intake and to promote autoimmunity via the Th17 cell axis. Here we demonstrate that high NaCl conditions induced a stable, pathogen-specific, anti-inflammatory Th17 cell fate in human T cells in vitro. The p38/MAPK pathway, involving NFAT5 and SGK1, regulated FoxP3 and interleukin (IL)-17A-expression in high-NaCl conditions. The NaCl-induced acquisition of an anti-inflammatory Th17 cell fate was confirmed in vivo in an experimental autoimmune encephalomyelitis (EAE) mouse model, which demonstrated strongly reduced disease symptoms upon transfer of T cells polarized in high NaCl conditions. However, NaCl was coopted to promote murine and human Th17 cell pathogenicity, if T cell stimulation occurred in a pro-inflammatory and TGF-β-low cytokine microenvironment. Taken together, our findings reveal a context-dependent, dichotomous role for NaCl in shaping Th17 cell pathogenicity. NaCl might therefore prove beneficial for the treatment of chronic inflammatory diseases in combination with cytokine-blocking drugs.
en
American Society for Clinical Investigation
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Adaptive immunity
Immunology
Inflammation
T cells
Salt generates anti-inflammatory Th17 cells but amplifies their pathogenicity in pro-inflammatory cytokine microenvironments.
Article
The Journal of clinical investigation
United States
2020-06-25T14:18:44Z
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oai:repository.helmholtz-hzi.de:10033/622314
2020-06-26 02:39:29.333
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6224332020-09-28T10:51:11Zcom_10033_128109com_10033_620659com_10033_6839com_10033_620618col_10033_128110col_10033_620660col_10033_621495col_10033_620621
Bonifacius, Agnes
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Goldmann, Oliver
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Floess, Stefan
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Holtfreter, Silva
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Robert, Philippe A
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Nordengrün, Maria
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Kruse, Friederike
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Lochner, Matthias
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Falk, Christine S
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Schmitz, Ingo
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Bröker, Barbara M
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Medina, Eva
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http://orcid.org/0000-0001-9073-0223
Huehn, Jochen
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http://orcid.org/0000-0001-8071-1379
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2020-09-10T07:20:07Z
2020-09-10T07:20:07Z
2020-08-07
Front Immunol. 2020;11:1579. Published 2020 Aug 7. doi:10.3389/fimmu.2020.01579.
32849537
10.3389/fimmu.2020.01579
http://hdl.handle.net/10033/622433
1664-3224
Frontiers in immunology
Staphylococcus aureus can cause life-threatening diseases, and hospital- as well as community-associated antibiotic-resistant strains are an emerging global public health problem. Therefore, prophylactic vaccines or immune-based therapies are considered as alternative treatment opportunities. To develop such novel treatment approaches, a better understanding of the bacterial virulence and immune evasion mechanisms and their potential effects on immune-based therapies is essential. One important staphylococcal virulence factor is alpha-toxin, which is able to disrupt the epithelial barrier in order to establish infection. In addition, alpha-toxin has been reported to modulate other cell types including immune cells. Since CD4+ T cell-mediated immunity is required for protection against S. aureus infection, we were interested in the ability of alpha-toxin to directly modulate CD4+ T cells. To address this, murine naïve CD4+ T cells were differentiated in vitro into effector T cell subsets in the presence of alpha-toxin. Interestingly, alpha-toxin induced death of Th1-polarized cells, while cells polarized under Th17 conditions showed a high resistance toward increasing concentrations of this toxin. These effects could neither be explained by differential expression of the cellular alpha-toxin receptor ADAM10 nor by differential activation of caspases, but might result from an increased susceptibility of Th1 cells toward Ca2+-mediated activation-induced cell death. In accordance with the in vitro findings, an alpha-toxin-dependent decrease of Th1 and concomitant increase of Th17 cells was observed in vivo during S. aureus bacteremia. Interestingly, corresponding subsets of innate lymphoid cells and γδ T cells were similarly affected, suggesting a more general effect of alpha-toxin on the modulation of type 1 and type 3 immune responses. In conclusion, we have identified a novel alpha-toxin-dependent immunomodulatory strategy of S. aureus, which can directly act on CD4+ T cells and might be exploited for the development of novel immune-based therapeutic approaches to treat infections with antibiotic-resistant S. aureus strains.
en
Frontiers
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
CD4+ T cells
Staphylococcus aureus
alpha-toxin
innate lymphoid cells
γδ T cells
Staphylococcus aureus Alpha-Toxin Limits Type 1 While Fostering Type 3 Immune Responses.
Article
11
1579
Frontiers in immunology
Switzerland
2020-09-10T07:20:07Z
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10033/622433
oai:repository.helmholtz-hzi.de:10033/622433
2020-09-28 10:51:11.932
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6225402020-11-04T04:36:51Zcom_10033_128109col_10033_128110
Zou, Mangge
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Yang, Juhao
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Wiechers, Carolin
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Huehn, Jochen
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HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2020-10-27T13:32:21Z
2020-10-27T13:32:21Z
2020-06-19
Eur J Microbiol Immunol (Bp). 2020 Jun 19;10(2):98–106. doi: 10.1556/1886.2020.00007.
2062-509X
32644940
10.1556/1886.2020.00007
http://hdl.handle.net/10033/622540
European journal of microbiology & immunology
Listeria monocytogenes (Lm) is a food-borne pathogen with a high chance of infecting neonates, pregnant women, elderly and immunocompromised individuals. Lm infection in neonates can cause neonatal meningitis and sepsis with a high risk of severe neurological and developmental sequelae and high mortality rates. However, whether an acute neonatal Lm infection causes long-term effects on the immune system persisting until adulthood has not been fully elucidated. Here, we established a neonatal Lm infection model and monitored the composition of major immune cell subsets at defined time points post infection (p.i.) in secondary lymphoid organs and the intestine. Twelve weeks p.i., the CD8+ T cell population was decreased in colon and mesenteric lymph nodes (mLNs) with an opposing increase in the spleen. In the colon, we observed an accumulation of CD4+ and CD8+ effector/memory T cells with an increase of T-bet+ T helper 1 (Th1) cells. In addition, 12 weeks p.i. an altered composition of innate lymphoid cell (ILC) and dendritic cell (DC) subsets was still observed in colon and mLNs, respectively. Together, these findings highlight organ-specific long-term consequences of an acute neonatal Lm infection on both the adaptive and innate immune system.
en
Akadémiai Kiadó
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
immune system
listeria monocytogenes
long-term consequences
neonatal infection
organ-specific
Acute neonatal Listeria monocytogenes infection causes long-term, organ-specific changes in immune cell subset composition.
Article
European journal of microbiology & immunology
Hungary
2020-10-27T13:32:21Z
THUMBNAIL
Zou, Yang, Wiechers and Hühn.pdf.jpg
Zou, Yang, Wiechers and Hühn.pdf.jpg
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Zou, Yang, Wiechers and Hühn.pdf.txt
Zou, Yang, Wiechers and Hühn.pdf.txt
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Zou, Yang, Wiechers and Hühn.pdf
Zou, Yang, Wiechers and Hühn.pdf
Open Access publication
application/pdf
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oai:repository.helmholtz-hzi.de:10033/622540
2020-11-04 04:36:51.062
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6227482021-02-18T04:37:51Zcom_10033_128109col_10033_128110
Permanyer, Marc
61c741796e387725063976751b1546b1
300
Bošnjak, Berislav
c6ead62d0c85b64d1438f3ceb9bd007c
300
Glage, Silke
57504ff77f40e1bac288596e3e9f9ae7
500
Friedrichsen, Michaela
9a232e3c23344e6e02077e2597ba77cd
300
Floess, Stefan
5ffe089d50f6ea39d568657c60ebcc8f
500
Huehn, Jochen
593aa066bacc8199a66ef7fe31379623
600
http://orcid.org/0000-0001-8071-1379
Patzer, Gwendolyn E
d33a9e580eed167554d3ede70d516368
300
Odak, Ivan
32a6b93e84b00ce2e98816b5e27f6d76
500
Eckert, Nadine
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300
Zargari, Razieh
57f596e13fd791f4453b1c55f87211ce
300
Ospina-Quintero, Laura
57c27452ee4a3591b27ef7f3dd735696
300
Georgiev, Hristo
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Förster, Reinhold
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500
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2021-02-17T16:34:24Z
2021-02-17T16:34:24Z
2021-01-06
Cell Mol Immunol. 2021 Feb;18(2):398-414. doi: 10.1038/s41423-020-00599-z. Epub 2021 Jan
33408345
10.1038/s41423-020-00599-z
http://hdl.handle.net/10033/622748
2042-0226
Cellular & molecular immunology
Signaling via interleukin-2 receptor (IL-2R) is a requisite for regulatory T (Treg) cell identity and function. However, it is not completely understood to what degree IL-2R signaling is required for Treg cell homeostasis, lineage stability and function in both resting and inflammatory conditions. Here, we characterized a spontaneous mutant mouse strain endowed with a hypomorphic Tyr129His variant of CD25, the α-chain of IL-2R, which resulted in diminished receptor expression and reduced IL-2R signaling. Under noninflammatory conditions, Cd25Y129H mice harbored substantially lower numbers of peripheral Treg cells with stable Foxp3 expression that prevented the development of spontaneous autoimmune disease. In contrast, Cd25Y129H Treg cells failed to efficiently induce immune suppression and lost lineage commitment in a T-cell transfer colitis model, indicating that unimpaired IL-2R signaling is critical for Treg cell function in inflammatory environments. Moreover, single-cell RNA sequencing of Treg cells revealed that impaired IL-2R signaling profoundly affected the balance of central and effector Treg cell subsets. Thus, partial loss of IL-2R signaling differentially interferes with the maintenance, heterogeneity, and suppressive function of the Treg cell pool.
en
Springer Nature
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
IL-2R signaling
Regulatory T cells
Treg heterogeneity
scRNA sequencing
Efficient IL-2R signaling differentially affects the stability, function, and composition of the regulatory T-cell pool.
Article
18
2
398
414
Cellular & molecular immunology
China
2021-02-17T16:34:24Z
THUMBNAIL
Permanyer et al.pdf.jpg
Permanyer et al.pdf.jpg
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Permanyer et al.pdf.txt
Permanyer et al.pdf.txt
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LICENSE
license.txt
license.txt
text/plain
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MD5
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CC-LICENSE
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ORIGINAL
Permanyer et al.pdf
Permanyer et al.pdf
Open Access publication
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https://repository.helmholtz-hzi.de/bitstream/10033/622748/1/Permanyer%20et%20al.pdf
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10033/622748
oai:repository.helmholtz-hzi.de:10033/622748
2021-02-18 04:37:51.848
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6228122021-04-01T01:31:51Zcom_10033_128109col_10033_128110
Zou, Mangge
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Wiechers, Carolin
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Huehn, Jochen
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500
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2021-03-31T14:48:31Z
2021-03-31T14:48:31Z
2021-02-25
Int J Med Microbiol. 2021 Feb 25;311(3):151492. doi: 10.1016/j.ijmm.2021.151492. Epub ahead of print.
33676241
10.1016/j.ijmm.2021.151492
http://hdl.handle.net/10033/622812
1618-0607
International journal of medical microbiology : IJMM
The effective priming of adaptive immune responses depends on the precise dispatching of lymphocytes and antigens into and within lymph nodes (LNs), which are strategically dispersed throughout the body. Over the past decade, a growing body of evidence has advanced our understanding of lymph node stromal cells (LNSCs) from viewing them as mere accessory cells to seeing them as critical cellular players for the modulation of adaptive immune responses. In this review, we summarize current advances on the pivotal roles that LNSCs play in orchestrating adaptive immune responses during homeostasis and infection, and highlight the imprinting of location-specific information by micro-environmental cues into LNSCs, thereby tailoring tissue-specific immune responses.
en
Elsevier
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
Immune regulation
Infection and inflammation
Lymph node
Mucosal micro-environment
Stromal cells
Lymph node stromal cell subsets-Emerging specialists for tailored tissue-specific immune responses.
Article
311
3
151492
International journal of medical microbiology : IJMM
Germany
2021-03-31T14:48:31Z
THUMBNAIL
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Zou, Wiechers and Huehn.pdf.jpg
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Zou, Wiechers and Huehn.pdf.txt
Zou, Wiechers and Huehn.pdf.txt
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https://repository.helmholtz-hzi.de/bitstream/10033/622812/4/Zou%2c%20Wiechers%20and%20Huehn.pdf.txt
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CC-LICENSE
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https://repository.helmholtz-hzi.de/bitstream/10033/622812/2/license_rdf
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ORIGINAL
Zou, Wiechers and Huehn.pdf
Zou, Wiechers and Huehn.pdf
Open Access publication
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https://repository.helmholtz-hzi.de/bitstream/10033/622812/1/Zou%2c%20Wiechers%20and%20Huehn.pdf
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1
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10033/622812
oai:repository.helmholtz-hzi.de:10033/622812
2021-04-01 01:31:51.801
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6228232021-04-08T01:40:59Zcom_10033_128109com_10033_620659com_10033_620591col_10033_128110col_10033_620724col_10033_620660
Elfaki, Yassin
b7ac992d2de87d19940f2622e92869f0
500
Robert, Philippe A
b943b7622feddf538cc52c707cf425b5
500
Binz, Christoph
f3fc7a6581143e981a0c1b32854ee552
300
Falk, Christine S
84fa0c3390a25e71bc272964dddb40ff
Bruder, Dunja
b5a4f0fe11461388fa1e79487e3fb00e
600
http://orcid.org/0000-0003-3066-189X
Prinz, Immo
4a3aae181793927d1b7907eb1a77b222
500
Floess, Stefan
5ffe089d50f6ea39d568657c60ebcc8f
500
Meyer-Hermann, Michael
f054b81293a071d59f3be787198a3299
Huehn, Jochen
81855dd40035a02edad8ee83ce210282
500
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany.
2021-04-07T14:24:38Z
2021-04-07T14:24:38Z
2021-02-26
Eur J Immunol. 2021 Feb 26. doi: 10.1002/eji.202048981. Epub ahead of print.
33638148
10.1002/eji.202048981
http://hdl.handle.net/10033/622823
1521-4141
European journal of immunology
Foxp3+ Treg cells, which are crucial for maintenance of self-tolerance, mainly develop within the thymus, where they arise from CD25+ Foxp3- or CD25- Foxp3+ Treg cell precursors. Although it is known that infections can cause transient thymic involution, the impact of infection-induced thymus atrophy on thymic Treg (tTreg) cell development is unknown. Here, we infected mice with influenza A virus (IAV) and studied thymocyte population dynamics post infection. IAV infection caused a massive, but transient thymic involution, dominated by a loss of CD4+ CD8+ double-positive (DP) thymocytes, which was accompanied by a significant increase in the frequency of CD25+ Foxp3+ tTreg cells. Differential apoptosis susceptibility could be experimentally excluded as a reason for the relative tTreg cell increase, and mathematical modeling suggested that enhanced tTreg cell generation cannot explain the increased frequency of tTreg cells. Yet, an increased death of DP thymocytes and augmented exit of single-positive (SP) thymocytes was suggested to be causative. Interestingly, IAV-induced thymus atrophy resulted in a significantly reduced T-cell receptor (TCR) repertoire diversity of newly produced tTreg cells. Taken together, IAV-induced thymus atrophy is substantially altering the dynamics of major thymocyte populations, finally resulting in a relative increase of tTreg cells with an altered TCR repertoire.
en
Wiley-VCH
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
Foxp3+ Treg cells ⋅ Influenza A virus ⋅ Mathematical modeling ⋅ Ordinary differential equations ⋅ Thymus atrophy
Influenza A virus-induced thymus atrophy differentially affects dynamics of conventional and regulatory T-cell development in mice.
Article
European journal of immunology
Germany
2021-04-07T14:24:38Z
THUMBNAIL
Elfaki et al.pdf.jpg
Elfaki et al.pdf.jpg
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MD5
5
false
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Elfaki et al.pdf.txt
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https://repository.helmholtz-hzi.de/bitstream/10033/622823/2/license_rdf
0175ea4a2d4caec4bbcc37e300941108
MD5
2
false
ORIGINAL
Elfaki et al.pdf
Elfaki et al.pdf
Open Access publication
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https://repository.helmholtz-hzi.de/bitstream/10033/622823/1/Elfaki%20et%20al.pdf
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MD5
1
true
10033/622823
oai:repository.helmholtz-hzi.de:10033/622823
2021-04-08 01:40:59.35
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6228512021-04-30T01:45:10Zcom_10033_128109com_10033_621723col_10033_621724col_10033_128110
Delacher, Michael
c35f7faaf1480d2966a72385664e22ce
500
Simon, Malte
44b4ed191aa48db14ca4a6c869180c35
300
Sanderink, Lieke
399f00d61668c24aad1feb139f7029c8
300
Hotz-Wagenblatt, Agnes
d20e787cd1bace565cb21b238bda9bd0
300
Wuttke, Marina
e08fa1d24d488d589bf3eb739a03f535
300
Schambeck, Kathrin
11eded4d273ce63075de7e6089ef1937
300
Schmidleithner, Lisa
f80b307d3ca66be374f309b39b367c34
300
Bittner, Sebastian
872f4147b485fdb698a9dd3190d74360
300
Pant, Asmita
45f15d005b6ceb9cedfac8d33a36d753
300
Ritter, Uwe
a6e1de86d7c00a1035cd401290211602
300
Hehlgans, Thomas
080579e39ce4344ee998978becd63c40
300
Riegel, Dania
0d013c0c104bd3606d1e90bdb1d47f72
300
Schneider, Verena
971397605b3fa7e0907636ed29c9bae2
300
Groeber-Becker, Florian Kai
413cb332a48d0d9125462408a29ef181
300
Eigenberger, Andreas
b5346a6b5610457c984b297795ce137d
300
Gebhard, Claudia
099a7cb6fccafc7b535e9712ede5b02d
300
Strieder, Nicholas
9aac6b67e142c2a0839bd4a6c3599b8d
300
Fischer, Alexander
9c106d80b069d99617b598221c67831d
300
Rehli, Michael
32c8e72a098ca6437b70b8b93f53d8e7
500
Hoffmann, Petra
7cd9b8ee73d688ff7972e744e97b0c5e
500
Edinger, Matthias
800064752a24cd72977cf61a79e187a2
500
Strowig, Till
10e75a13bdf38eace0268c245f4091a3
500
Huehn, Jochen
593aa066bacc8199a66ef7fe31379623
600
http://orcid.org/0000-0001-8071-1379
Schmidl, Christian
02e044df9ed49291ba111e7e9a2f7e0d
300
Werner, Jens M
992fac8bc4cc433e8ca3bc01bb91f307
300
Prantl, Lukas
bc4384fd910adfe17494e5f9c177e6f6
300
Brors, Benedikt
2956f9b400f4c137dfaca60cb72257b2
500
Imbusch, Charles D
f9eccea78121d4ad2e02613ab5c13ef1
300
Feuerer, Markus
2a226cb824e1a1bb38bd65bd10cb0708
500
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2021-04-29T07:07:00Z
2021-04-29T07:07:00Z
2021-03-30
Immunity. 2021 Apr 13;54(4):702-720.e17. doi: 10.1016/j.immuni.2021.03.007. Epub 2021 Mar 30.
33789089
10.1016/j.immuni.2021.03.007
http://hdl.handle.net/10033/622851
1097-4180
Immunity
Murine regulatory T (Treg) cells in tissues promote tissue homeostasis and regeneration. We sought to identify features that characterize human Treg cells with these functions in healthy tissues. Single-cell chromatin accessibility profiles of murine and human tissue Treg cells defined a conserved, microbiota-independent tissue-repair Treg signature with a prevailing footprint of the transcription factor BATF. This signature, combined with gene expression profiling and TCR fate mapping, identified a population of tissue-like Treg cells in human peripheral blood that expressed BATF, chemokine receptor CCR8 and HLA-DR. Human BATF+CCR8+ Treg cells from normal skin and adipose tissue shared features with nonlymphoid T follicular helper-like (Tfh-like) cells, and induction of a Tfh-like differentiation program in naive human Treg cells partially recapitulated tissue Treg regenerative characteristics, including wound healing potential. Human BATF+CCR8+ Treg cells from healthy tissue share features with tumor-resident Treg cells, highlighting the importance of understanding the context-specific functions of these cells.
en
Cell Press
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
Single-cell chromatin accessibility landscape identifies tissue repair program in human regulatory T cells.
Article
54
4
702
720.e17
Immunity
United States
2021-04-29T07:07:00Z
THUMBNAIL
Delacher et al.pdf.jpg
Delacher et al.pdf.jpg
Generated Thumbnail
image/jpeg
106630
https://repository.helmholtz-hzi.de/bitstream/10033/622851/5/Delacher%20et%20al.pdf.jpg
aeb84a60e28fea21f16f014fbde01a32
MD5
5
false
elsevier-thumbnail.png
application/octet-stream
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https://repository.helmholtz-hzi.de/bitstream/10033/622851/6/elsevier-thumbnail.png
86b194c7722c5fb238dbd0c0d3bb9356
MD5
6
false
TEXT
Delacher et al.pdf.txt
Delacher et al.pdf.txt
Extracted text
text/plain
152498
https://repository.helmholtz-hzi.de/bitstream/10033/622851/4/Delacher%20et%20al.pdf.txt
128d5bd78c19d4f3ed201fa42d0ba43b
MD5
4
false
LICENSE
license.txt
license.txt
text/plain
1685
https://repository.helmholtz-hzi.de/bitstream/10033/622851/3/license.txt
cb598eeb10bfed09d26fd8d285172ad4
MD5
3
false
CC-LICENSE
license_rdf
license_rdf
application/rdf+xml; charset=utf-8
908
https://repository.helmholtz-hzi.de/bitstream/10033/622851/2/license_rdf
0175ea4a2d4caec4bbcc37e300941108
MD5
2
false
ORIGINAL
Delacher et al.pdf
Delacher et al.pdf
Open Access publication
application/pdf
22189690
https://repository.helmholtz-hzi.de/bitstream/10033/622851/1/Delacher%20et%20al.pdf
f9f006ea1d4a33464ad9603ab568185c
MD5
1
true
10033/622851
oai:repository.helmholtz-hzi.de:10033/622851
2021-04-30 01:45:10.22
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6228592021-05-07T01:42:01Zcom_10033_128109col_10033_128110
Maus, Irena
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Klocke, Michael
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Derenkó, Jaqueline
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Stolze, Yvonne
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Beckstette, Michael
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Jost, Carsten
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500
Wibberg, Daniel
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500
Blom, Jochen
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Henke, Christian
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Willenbücher, Katharina
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Rumming, Madis
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Rademacher, Antje
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Pühler, Alfred
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Sczyrba, Alexander
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Schlüter, Andreas
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HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2021-05-06T15:17:02Z
2021-05-06T15:17:02Z
2020-03-02
Environ Microbiome. 2020 Mar 2;15(1):7. doi: 10.1186/s40793-020-00354-x.
33902713
10.1186/s40793-020-00354-x
http://hdl.handle.net/10033/622859
2524-6372
Environmental microbiome
Background: Anaerobic digestion (AD) of protein-rich grass silage was performed in experimental two-stage two-phase biogas reactor systems at low vs. increased organic loading rates (OLRs) under mesophilic (37 °C) and thermophilic (55 °C) temperatures. To follow the adaptive response of the biomass-attached cellulolytic/hydrolytic biofilms at increasing ammonium/ammonia contents, genome-centered metagenomics and transcriptional profiling based on metagenome assembled genomes (MAGs) were conducted.
Results: In total, 78 bacterial and archaeal MAGs representing the most abundant members of the communities, and featuring defined quality criteria were selected and characterized in detail. Determination of MAG abundances under the tested conditions by mapping of the obtained metagenome sequence reads to the MAGs revealed that MAG abundance profiles were mainly shaped by the temperature but also by the OLR. However, the OLR effect was more pronounced for the mesophilic systems as compared to the thermophilic ones. In contrast, metatranscriptome mapping to MAGs subsequently normalized to MAG abundances showed that under thermophilic conditions, MAGs respond to increased OLRs by shifting their transcriptional activities mainly without adjusting their proliferation rates. This is a clear difference compared to the behavior of the microbiome under mesophilic conditions. Here, the response to increased OLRs involved adjusting of proliferation rates and corresponding transcriptional activities. The analysis led to the identification of MAGs positively responding to increased OLRs. The most outstanding MAGs in this regard, obviously well adapted to higher OLRs and/or associated conditions, were assigned to the order Clostridiales (Acetivibrio sp.) for the mesophilic biofilm and the orders Bacteroidales (Prevotella sp. and an unknown species), Lachnospirales (Herbinix sp. and Kineothrix sp.) and Clostridiales (Clostridium sp.) for the thermophilic biofilm. Genome-based metabolic reconstruction and transcriptional profiling revealed that positively responding MAGs mainly are involved in hydrolysis of grass silage, acidogenesis and / or acetogenesis.
Conclusions: An integrated -omics approach enabled the identification of new AD biofilm keystone species featuring outstanding performance under stress conditions such as increased OLRs. Genome-based knowledge on the metabolic potential and transcriptional activity of responsive microbiome members will contribute to the development of improved microbiological AD management strategies for biomethanation of renewable biomass.
en
BMC
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
Anaerobic digestion
Bioconversion
Biogas
Integrated -omics
Metabolic activity
Metagenome assembled genomes
Methane
Microbial community structure
Polyomics
Impact of process temperature and organic loading rate on cellulolytic / hydrolytic biofilm microbiomes during biomethanation of ryegrass silage revealed by genome-centered metagenomics and metatranscriptomics.
Article
15
1
7
Environmental microbiome
England
2021-05-06T15:17:02Z
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10033/622859
oai:repository.helmholtz-hzi.de:10033/622859
2021-05-07 01:42:01.867
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6228902021-06-01T01:45:47Zcom_10033_128109com_10033_621723col_10033_621724col_10033_128110
Wiechers, Carolin
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500
Zou, Mangge
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500
Galvez, Eric
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500
Beckstette, Michael
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500
Ebel, Maria
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Strowig, Till
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http://orcid.org/0000-0003-0185-1459
Huehn, Jochen
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Pezoldt, Joern
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HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2021-05-31T12:18:34Z
2021-05-31T12:18:34Z
2021-03-24
Cell Mol Immunol. 2021 May;18(5):1211-1221. doi: 10.1038/s41423-021-00647-2. Epub 2021 Mar 24.
33762684
10.1038/s41423-021-00647-2
http://hdl.handle.net/10033/622890
2042-0226
Cellular & molecular immunology
Intestinal Foxp3+ regulatory T cell (Treg) subsets are crucial players in tolerance to microbiota-derived and food-borne antigens, and compelling evidence suggests that the intestinal microbiota modulates their generation, functional specialization, and maintenance. Selected bacterial species and microbiota-derived metabolites, such as short-chain fatty acids (SCFAs), have been reported to promote Treg homeostasis in the intestinal lamina propria. Furthermore, gut-draining mesenteric lymph nodes (mLNs) are particularly efficient sites for the generation of peripherally induced Tregs (pTregs). Despite this knowledge, the direct role of the microbiota and their metabolites in the early stages of pTreg induction within mLNs is not fully elucidated. Here, using an adoptive transfer-based pTreg induction system, we demonstrate that neither transfer of a dysbiotic microbiota nor dietary SCFA supplementation modulated the pTreg induction capacity of mLNs. Even mice housed under germ-free (GF) conditions displayed equivalent pTreg induction within mLNs. Further molecular characterization of these de novo induced pTregs from mLNs by dissection of their transcriptomes and accessible chromatin regions revealed that the microbiota indeed has a limited impact and does not contribute to the initialization of the Treg-specific epigenetic landscape. Overall, our data suggest that the microbiota is dispensable for the early stages of pTreg induction within mLNs.
en
Springer Nature
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
Microbiota
Peripheral regulatory T cells
Tolerance
The microbiota is dispensable for the early stages of peripheral regulatory T cell induction within mesenteric lymph nodes.
Article
18
5
1211
1221
Cellular & molecular immunology
China
2021-05-31T12:18:34Z
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Wiechers et al.pdf
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Open Access publication
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10033/622890
oai:repository.helmholtz-hzi.de:10033/622890
2021-06-01 01:45:47.75
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6229102021-06-25T01:42:23Zcom_10033_128109col_10033_128110
Floess, Stefan
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500
Huehn, Jochen
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600
http://orcid.org/0000-0001-8071-1379
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2021-06-24T15:34:11Z
2021-06-24T15:34:11Z
2021-04-30
Methods Mol Biol. 2021;2285:265-276. doi: 10.1007/978-1-0716-1311-5_21.
33928559
10.1007/978-1-0716-1311-5_21
http://hdl.handle.net/10033/622910
1940-6029
Methods in molecular biology (Clifton, N.J.)
The comparison of methylomes from immune cells enables the identification of differentially methylated regions and thereby region-associated gene loci. Those regions can be used to discriminate one immune cell population from the other, as well as help to identify key molecules and major pathways determining the unique phenotypes of immune cell lineages. The combination of bisulfite treatment of genomic DNA and next-generation sequencing provides the basis for studying epigenetic changes in different immune cell populations. Further development of whole-genome bisulfite sequencing resulted in a protocol for sequencing libraries that accept both single- or double-stranded DNA from fixed or nonfixed cells, respectively. Therefore, researchers can include immune cell populations in their methylation studies whose isolation depends on the staining of intracellular molecules.
en
Springer Nature
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
Epigenetic regulation
Methylome
Sequencing library
Generation of Sequencing Libraries for Building Immune Cell Methylomes.
Article
Book chapter
2285
265
276
Methods in molecular biology (Clifton, N.J.)
United States
THUMBNAIL
2022-04-30
Floess and Hühn.pdf.jpg
Floess and Hühn.pdf.jpg
Generated Thumbnail
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TEXT
2022-04-30
Floess and Hühn.pdf.txt
Floess and Hühn.pdf.txt
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ORIGINAL
Floess and Hühn.pdf
Floess and Hühn.pdf
accepted manuscript
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10033/622910
oai:repository.helmholtz-hzi.de:10033/622910
2021-06-25 01:42:23.703
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6229532021-07-23T01:43:30Zcom_10033_128109col_10033_128110
Ciurkiewicz, Malgorzata
ef195e4a3e57f07591376261aabbe6e6
500
Floess, Stefan
5ffe089d50f6ea39d568657c60ebcc8f
500
Beckstette, Michael
530851ef69d811ebaec33bc7728233b1
500
Kummerfeld, Maren
3a0b5eb5f299bdfa55774c566c3b9a6b
500
Baumgärtner, Wolfgang
fe2686afc5eb082abd274fc5a6af1f60
500
Huehn, Jochen
593aa066bacc8199a66ef7fe31379623
600
http://orcid.org/0000-0001-8071-1379
Beineke, Andreas
fd6611aa04d8fb9b4f2a7118e42a818a
500
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2021-07-22T14:22:33Z
2021-07-22T14:22:33Z
2021-07-06
Brain Pathol. 2021 Jul 6:e13000. doi: 10.1111/bpa.13000. Epub ahead of print.
34231271
10.1111/bpa.13000
http://hdl.handle.net/10033/622953
1750-3639
Brain pathology (Zurich, Switzerland)
Viral infections of the central nervous system cause acute or delayed neuropathology and clinical consequences ranging from asymptomatic courses to chronic, debilitating diseases. The outcome of viral encephalitis is partially determined by genetically programed immune response patterns of the host. Experimental infection of mice with Theiler's murine encephalomyelitis virus (TMEV) causes diverse neurologic diseases, including TMEV-induced demyelinating disease (TMEV-IDD), depending on the used mouse strain. The aim of the present study was to compare initial transcriptomic changes occurring in the brain of TMEV-infected SJL (TMEV-IDD susceptible) and C57BL/6 (TMEV-IDD resistant) mice. Animals were infected with TMEV and sacrificed 4, 7, or 14 days post infection. RNA was isolated from brain tissue and analyzed by whole-transcriptome sequencing. Selected differences were confirmed on a protein level by immunohistochemistry. In mock-infected SJL and C57BL/6 mice, >200 differentially expressed genes (DEGs) were detected. Following TMEV-infection, the number of DEGs increased to >700. Infected C57BL/6 mice showed a higher expression of transcripts related to antigen presentation via major histocompatibility complex (MHC) I, innate antiviral immune responses and cytotoxicity, compared with infected SJL animals. Expression of many of those genes was weaker or delayed in SJL mice, associated with a failure of viral clearance in this mouse strain. SJL mice showed prolonged elevation of MHC II and chemotactic genes compared with C57BL/6 mice, which presumably facilitates the induction of chronic demyelinating disease. In addition, elevated expression of several genes associated with immunomodulatory or -suppressive functions was observed in SJL mice. The exploratory study confirms previous observations in the model and provides an extensive list of new immunologic parameters potentially contributing to different outcomes of viral encephalitis in two mouse strains.
en
Wiley & Sons Ltd.
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
Theiler's murine encephalomyelitis virus
antigen presentation
antiviral response
demyelination
innate immune response
mouse model
neurotropic virus
transcriptome analysis
viral encephalitis
Transcriptome analysis following neurotropic virus infection reveals faulty innate immunity and delayed antigen presentation in mice susceptible to virus-induced demyelination.
Article
e13000
Brain pathology (Zurich, Switzerland)
Switzerland
2021-07-22T14:22:33Z
THUMBNAIL
Ciurkiewicz et al.pdf.jpg
Ciurkiewicz et al.pdf.jpg
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TEXT
Ciurkiewicz et al.pdf.txt
Ciurkiewicz et al.pdf.txt
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LICENSE
license.txt
license.txt
text/plain
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https://repository.helmholtz-hzi.de/bitstream/10033/622953/3/license.txt
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MD5
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CC-LICENSE
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ORIGINAL
Ciurkiewicz et al.pdf
Ciurkiewicz et al.pdf
Open Access publication
application/pdf
2254572
https://repository.helmholtz-hzi.de/bitstream/10033/622953/1/Ciurkiewicz%20et%20al.pdf
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10033/622953
oai:repository.helmholtz-hzi.de:10033/622953
2021-07-23 01:43:30.646
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6230112021-09-02T02:41:49Zcom_10033_128109com_10033_622921col_10033_128110col_10033_622926
Elfaki, Yassin
b7ac992d2de87d19940f2622e92869f0
500
Yang, Juhao
43e66036634a4c27f99b1afc185e288f
500
Boehme, Julia
dc0b2f9a3bd7cb2063cb080f6c2468ae
Schultz, Kristin
cac36c3c13d2557c829190ce1be4f5b9
500
Bruder, Dunja
1ba4133d9ea07fbb30b11e97f4ab5bda
500
Falk, Christine S
84fa0c3390a25e71bc272964dddb40ff
Huehn, Jochen
81855dd40035a02edad8ee83ce210282
500
Floess, Stefan
5ffe089d50f6ea39d568657c60ebcc8f
500
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2021-09-01T11:36:54Z
2021-09-01T11:36:54Z
2021-07-14
Int J Mol Sci. 2021 Jul 14;22(14):7522. doi: 10.3390/ijms22147522.
34299148
10.3390/ijms22147522
http://hdl.handle.net/10033/623011
1422-0067
International journal of molecular sciences
During influenza A virus (IAV) infections, CD4+ T cell responses within infected lungs mainly involve T helper 1 (Th1) and regulatory T cells (Tregs). Th1-mediated responses favor the co-expression of T-box transcription factor 21 (T-bet) in Foxp3+ Tregs, enabling the efficient Treg control of Th1 responses in infected tissues. So far, the exact accumulation kinetics of T cell subsets in the lungs and lung-draining lymph nodes (dLN) of IAV-infected mice is incompletely understood, and the epigenetic signature of Tregs accumulating in infected lungs has not been investigated. Here, we report that the total T cell and the two-step Treg accumulation in IAV-infected lungs is transient, whereas the change in the ratio of CD4+ to CD8+ T cells is more durable. Within lungs, the frequency of Tregs co-expressing T-bet is steadily, yet transiently, increasing with a peak at Day 7 post-infection. Interestingly, T-bet+ Tregs accumulating in IAV-infected lungs displayed a strongly demethylated Tbx21 locus, similarly as in T-bet+ conventional T cells, and a fully demethylated Treg-specific demethylated region (TSDR) within the Foxp3 locus. In summary, our data suggest that T-bet+ but not T-bet- Tregs are epigenetically stabilized during IAV-induced infection in the lung.
en
MDPI
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
Foxp3
Tbx21
Tregs
inflammation
influenza A virus
lung
methylation
Tbx21 and foxp3 are Epigenetically Stabilized in T-Bet Tregs That Transiently Accumulate in Influenza A Virus-Infected Lungs.
Article
22
14
International journal of molecular sciences
Switzerland
2021-09-01T11:36:54Z
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10033/623011
oai:repository.helmholtz-hzi.de:10033/623011
2021-09-02 02:41:49.975
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6230172021-09-09T01:53:12Zcom_10033_128109com_10033_620659col_10033_128110col_10033_620660
Arulraj, Theinmozhi
7f81f4a361c7601256a026aefaf11acd
500
Binder, Sebastian C
ca9fc32341dea761712a6ca7f0d7308b
500
http://orcid.org/0000-0003-1169-1786
Robert, Philippe A
b943b7622feddf538cc52c707cf425b5
500
Meyer-Hermann, Michael
f054b81293a071d59f3be787198a3299
BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany.; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2021-09-08T12:17:09Z
2021-09-08T12:17:09Z
2021-07-07
Front Immunol. 2021 Jul 7;12:705240. doi: 10.3389/fimmu.2021.705240.
34305944
10.3389/fimmu.2021.705240
http://hdl.handle.net/10033/623017
1664-3224
Frontiers in immunology
Germinal Centres (GCs) are transient structures in secondary lymphoid organs, where affinity maturation of B cells takes place following an infection. While GCs are responsible for protective antibody responses, dysregulated GC reactions are associated with autoimmune disease and B cell lymphoma. Typically, 'normal' GCs persist for a limited period of time and eventually undergo shutdown. In this review, we focus on an important but unanswered question - what causes the natural termination of the GC reaction? In murine experiments, lack of antigen, absence or constitutive T cell help leads to premature termination of the GC reaction. Consequently, our present understanding is limited to the idea that GCs are terminated due to a decrease in antigen access or changes in the nature of T cell help. However, there is no direct evidence on which biological signals are primarily responsible for natural termination of GCs and a mechanistic understanding is clearly lacking. We discuss the present understanding of the GC shutdown, from factors impacting GC dynamics to changes in cellular interactions/dynamics during the GC lifetime. We also address potential missing links and remaining questions in GC biology, to facilitate further studies to promote a better understanding of GC shutdown in infection and immune dysregulation.
en
Frontiers
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
B cell lymphoma
antibody responses
chronic germinal centres
ectopic germinal centres
germinal centre shutdown
vaccination
Germinal Centre Shutdown.
Article
12
705240
Frontiers in immunology
Switzerland
2021-09-08T12:17:10Z
THUMBNAIL
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oai:repository.helmholtz-hzi.de:10033/623017
2021-09-09 01:53:12.362
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6230282021-09-15T01:54:16Zcom_10033_128109col_10033_128110
Shaikh, Haroon
1824f922dfee4673ed4c189c003d137f
500
Vargas, Juan Gamboa
f96072c2ea0855fda9d58afcfa6b4174
300
Mokhtari, Zeinab
3f01cf1b9b2bfe1649aedd4a71ec7a9d
300
Jarick, Katja J
92b714c55642cedfcfcea4cfe2134055
300
Ulbrich, Maria
d63e883bb3922ff018a0351d17c8351d
300
Mosca, Josefina Peña
ad521c1e3419db42a01dc779a49a1edd
300
Viera, Estibaliz Arellano
3551756af17bd2a0d17a92f1502e2389
300
Graf, Caroline
5801b102dc0c29b0a494f4b405f93927
300
Le, Duc-Dung
9ca581f8c24cdff282a94eae811d4eca
300
Heinze, Katrin G
d51e1f052ecf1c3ce27fd5e99cc85f42
300
Büttner-Herold, Maike
ae10764ba7fa936d74fe9ad3c755d831
300
Rosenwald, Andreas
f6f63441ebc0e45f270005c769646d18
500
Pezoldt, Joern
12528b25f15cd5d3e26390b9840374ee
500
Huehn, Jochen
593aa066bacc8199a66ef7fe31379623
600
http://orcid.org/0000-0001-8071-1379
Beilhack, Andreas
279ddcac70d6649b3da98cd7986186df
300
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
2021-09-14T09:43:47Z
2021-09-14T09:43:47Z
2021-07-26
Front Immunol. 2021 Jul 26;12:689896. doi: 10.3389/fimmu.2021.689896.
34381447
10.3389/fimmu.2021.689896
http://hdl.handle.net/10033/623028
1664-3224
Frontiers in immunology
Mesenteric lymph nodes (mLNs) are sentinel sites of enteral immunosurveillance and immune homeostasis. Immune cells from the gastrointestinal tract (GIT) are constantly recruited to the mLNs in steady-state and under inflammatory conditions resulting in the induction of tolerance and immune cells activation, respectively. Surgical dissection and transplantation of lymph nodes (LN) is a technique that has supported seminal work to study LN function and is useful to investigate resident stromal and endothelial cell biology and their cellular interactions in experimental disease models. Here, we provide a detailed protocol of syngeneic mLN transplantation and report assays to analyze effective mLN engraftment in congenic recipients. Transplanted mLNs allow to study T cell activation and proliferation in preclinical mouse models. Donor mLNs proved viable and functional after surgical transplantation and regenerated blood and lymphatic vessels. Immune cells from the host completely colonized the transplanted mLNs within 7-8 weeks after the surgical intervention. After allogeneic hematopoietic cell transplantation (allo-HCT), adoptively transferred allogeneic CD4+ T cells from FVB/N (H-2q) mice homed to the transplanted mLNs in C57BL/6 (H-2b) recipients during the initiation phase of acute graft-versus-host disease (aGvHD). These CD4+ T cells retained full proliferative capacity and upregulated effector and gut homing molecules comparable to those in mLNs from unmanipulated wild-type recipients. Wild type mLNs transplanted into MHCII deficient syngeneic hosts sufficed to activate alloreactive T cells upon allogeneic hematopoietic cell transplantation, even in the absence of MHCII+ CD11c+ myeloid cells. These data support that orthotopically transplanted mLNs maintain physiological functions after transplantation. The technique of LN transplantation can be applied to study migratory and resident cell compartment interactions in mLNs as well as immune reactions from and to the gut under inflammatory and non-inflammatory conditions.
en
Frontiers
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
acute graft-versus host disease
alloreactive T cells
lymph node stromal cells
lymph node transplantation
mesenteric lymph node
mouse models
Mesenteric Lymph Node Transplantation in Mice to Study Immune Responses of the Gastrointestinal Tract.
Article
12
689896
Frontiers in immunology
Switzerland
2021-09-14T09:43:47Z
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10033/623028
oai:repository.helmholtz-hzi.de:10033/623028
2021-09-15 01:54:16.791
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6231182021-12-14T03:20:36Zcom_10033_128109com_10033_620659col_10033_621771col_10033_128110col_10033_620660
Formaglio, Pauline
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Robert, Philippe A
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Bertrand, Jessica
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Kahlfuß, Sascha
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Bousso, Philippe
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Schraven, Burkhart
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Huehn, Jochen
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Binder, Sebastian
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Meyer-Hermann, Michael
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Müller, Andreas J
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BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38106 Braunschweig, Germany.
2021-12-13T14:09:55Z
2021-12-13T14:09:55Z
2021-10-15
mmunity. 2021 Oct 15:S1074-7613(21)00406-4. doi: 10.1016/j.immuni.2021.09.021. Epub ahead of print.
34687607
10.1016/j.immuni.2021.09.021
http://hdl.handle.net/10033/623118
1097-4180
Immunity
Nitric oxide (NO) is an important antimicrobial effector but also prevents unnecessary tissue damage by shutting down the recruitment of monocyte-derived phagocytes. Intracellular pathogens such as Leishmania major can hijack these cells as a niche for replication. Thus, NO might exert containment by restricting the availability of the cellular niche required for efficient pathogen proliferation. However, such indirect modes of action remain to be established. By combining mathematical modeling with intravital 2-photon biosensors of pathogen viability and proliferation, we show that low L. major proliferation results not from direct NO impact on the pathogen but from reduced availability of proliferation-permissive host cells. Although inhibiting NO production increases recruitment of these cells, and thus pathogen proliferation, blocking cell recruitment uncouples the NO effect from pathogen proliferation. Therefore, NO fulfills two distinct functions for L. major containment: permitting direct killing and restricting the supply of proliferation-permissive host cells.
en
Cell Press
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
2-photon microscopy
Leishmania
biosensor
iNOS
inflammation
intracellular pathogen
monocyte
nitric oxide
phagocyte
Nitric oxide controls proliferation of Leishmania major by inhibiting the recruitment of permissive host cells.
Article
Immunity
United States
2021-12-13T14:09:55Z
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Open Access article
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10033/623118
oai:repository.helmholtz-hzi.de:10033/623118
2021-12-14 03:20:36.909
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6231252021-12-22T01:49:29Zcom_10033_128109col_10033_128110
Ruck, Tobias
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Bock, Stefanie
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Pfeuffer, Steffen
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Schroeter, Christina B
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Cengiz, Derya
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Marciniak, Paul
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Lindner, Maren
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Herrmann, Alexander
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Liebmann, Marie
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Kovac, Stjepana
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Gola, Lukas
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Rolfes, Leoni
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Pawlitzki, Marc
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Opel, Nils
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Hahn, Tim
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Dannlowski, Udo
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Pap, Thomas
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Luessi, Felix
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Schreiber, Julian A
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Wünsch, Bernhard
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Kuhlmann, Tanja
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Seebohm, Guiscard
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Wischmeyer, Erhard
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Chasan, Achmet Imam
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Roth, Johannes
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Klotz, Luisa
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Meyer Zu Hörste, Gerd
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Wiendl, Heinz
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Marschall, Tobias
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Floess, Stefan
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Huehn, Jochen
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http://orcid.org/0000-0001-8071-1379
Budde, Thomas
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Bopp, Tobias
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Meuth, Sven G
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HZI, Helmholtz Zentrum für Infektionsforschung, GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2021-12-21T11:24:25Z
2021-12-21T11:24:25Z
2021-10-26
Cell Res. 2021 Oct 26:1–17. doi: 10.1038/s41422-021-00580-z. Epub ahead of print. PMID: 34702947.
34702947
10.1038/s41422-021-00580-z
http://hdl.handle.net/10033/623125
1748-7838
Cell research
It remains largely unclear how thymocytes translate relative differences in T cell receptor (TCR) signal strength into distinct developmental programs that drive the cell fate decisions towards conventional (Tconv) or regulatory T cells (Treg). Following TCR activation, intracellular calcium (Ca2+) is the most important second messenger, for which the potassium channel K2P18.1 is a relevant regulator. Here, we identify K2P18.1 as a central translator of the TCR signal into the thymus-derived Treg (tTreg) selection process. TCR signal was coupled to NF-κB-mediated K2P18.1 upregulation in tTreg progenitors. K2P18.1 provided the driving force for sustained Ca2+ influx that facilitated NF-κB- and NFAT-dependent expression of FoxP3, the master transcription factor for Treg development and function. Loss of K2P18.1 ion-current function induced a mild lymphoproliferative phenotype in mice, with reduced Treg numbers that led to aggravated experimental autoimmune encephalomyelitis, while a gain-of-function mutation in K2P18.1 resulted in increased Treg numbers in mice. Our findings in human thymus, recent thymic emigrants and multiple sclerosis patients with a dominant-negative missense K2P18.1 variant that is associated with poor clinical outcomes indicate that K2P18.1 also plays a role in human Treg development. Pharmacological modulation of K2P18.1 specifically modulated Treg numbers in vitro and in vivo. Finally, we identified nitroxoline as a K2P18.1 activator that led to rapid and reversible Treg increase in patients with urinary tract infections. Conclusively, our findings reveal how K2P18.1 translates TCR signals into thymic T cell fate decisions and Treg development, and provide a basis for the therapeutic utilization of Treg in several human disorders.
en
nATURE Publishing Group
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
K18.1 translates T cell receptor signals into thymic regulatory T cell development.
Article
Cell research
England
2021-12-21T11:24:26Z
THUMBNAIL
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Ruck et al.pdf.txt
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LICENSE
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ORIGINAL
Ruck et al.pdf
Ruck et al.pdf
Open Access publication
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10033/623125
oai:repository.helmholtz-hzi.de:10033/623125
2021-12-22 01:49:29.458
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6231902022-05-11T01:55:48Zcom_10033_128109col_10033_128110
Saleh, Reem
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Sasidharan Nair, Varun
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Toor, Salman M.
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Elkord, Eyad
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Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia; Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar;Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany; Biomedical Research Center, School of Science, Engineering and Environment, University of Salford, Manchester, United Kingdom; College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Doha, Qatar;Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Oman
2022-05-10T08:52:24Z
2022-05-10T08:52:24Z
2021-08-27
Reem Saleh, Varun Sasidharan Nair, Salman M. Toor, Eyad Elkord, Chapter Fourteen - Intrinsic and acquired cancer immunotherapy resistance, Editor(s): Mansoor M. Amiji, Lara Scheherazade Milane, Cancer Immunology and Immunotherapy, Academic Press, 2022, Pages 463-497, ISBN 9780128233979, https://doi.org/10.1016/B978-0-12-823397-9.00014-4. (https://www.sciencedirect.com/science/article/pii/B9780128233979000144) Abstract: Cancer immunotherapies, such as immune checkpoint inhibitors (ICIs), have revolutionized the treatment of various cancers and have shown a great efficacy in inducing antitumor immunity. Cancer immunotherapy in the form of adoptive cell transfer (ACT) have also been developed to eradicate tumor cells in a specific and effective manner, and it includes the administration of autologous tumor-infiltrating T-cells (TILs), T-cell receptor (TCR)-modified T-cells, or genetically engineered chimeric antigen receptor (CAR)-specific T-cells (CARTs) in cancer patients. Additionally, cancer vaccines and recombinant cytokines can be used as monotherapy or adjuvant therapy. Despite the success of immunotherapies in treating various solid tumors and hematologic malignancies, a significant number of patients do not benefit from these therapies and exhibit limited or no response. Some cancer patients do not respond to immunotherapies as a result of primary or intrinsic tumor resistance, while others respond to immunotherapies but develop resistance over time, referred to as adaptive or acquired tumor resistance. Tumor intrinsic- and extrinsic-mediated mechanisms, including genetic and epigenetic alterations, tumor-mutational loads, overexpression of co-inhibitory immune checkpoints, and elevated levels of suppressive immune cells and cytokines, can lead to a compromised antitumor immunity favoring tumorigenesis and cancer progression. This chapter outlines mechanisms of intrinsic tumor resistance and the emergence of acquired tumor resistance to cancer immunotherapies. Moreover, this chapter describes combined cancer immunotherapies, which may offer a great therapeutic potential to overcome tumor resistance against therapy and improve clinical outcomes in cancer patients. Keywords: Cancer; Immunotherapy; Immune checkpoint inhibitor; Adoptive T-cell therapy; Tumor microenvironment; Intrinsic resistance; Acquired resistance; Epigenetics; Therapeutic strategies
978-0-12823397-9
10.1016/B978-0-12-823397-9.00014-4
http://hdl.handle.net/10033/623190
Cancer Immunology and Immunotherapy: Volume 1 of Delivery Strategies and Engineering Technologies in Cancer Immunotherapy
2-s2.0-85127689292
SCOPUS_ID:85127689292
Cancer immunotherapies, such as immune checkpoint inhibitors (ICIs), have revolutionized the treatment of various cancers and have shown a great efficacy in inducing antitumor immunity. Cancer immunotherapy in the form of adoptive cell transfer (ACT) have also been developed to eradicate tumor cells in a specific and effective manner, and it includes the administration of autologous tumor-infiltrating T-cells (TILs), T-cell receptor (TCR)-modified T-cells, or genetically engineered chimeric antigen receptor (CAR)-specific T-cells (CARTs) in cancer patients. Additionally, cancer vaccines and recombinant cytokines can be used as monotherapy or adjuvant therapy. Despite the success of immunotherapies in treating various solid tumors and hematologic malignancies, a significant number of patients do not benefit from these therapies and exhibit limited or no response. Some cancer patients do not respond to immunotherapies as a result of primary or intrinsic tumor resistance, while others respond to immunotherapies but develop resistance over time, referred to as adaptive or acquired tumor resistance. Tumor intrinsic- and extrinsic-mediated mechanisms, including genetic and epigenetic alterations, tumor-mutational loads, overexpression of co-inhibitory immune checkpoints, and elevated levels of suppressive immune cells and cytokines, can lead to a compromised antitumor immunity favoring tumorigenesis and cancer progression. This chapter outlines mechanisms of intrinsic tumor resistance and the emergence of acquired tumor resistance to cancer immunotherapies. Moreover, this chapter describes combined cancer immunotherapies, which may offer a great therapeutic potential to overcome tumor resistance against therapy and improve clinical outcomes in cancer patients. +é(c) 2022 Elsevier Inc. All rights reserved
Cancer immunotherapies, such as immune checkpoint inhibitors (ICIs), have revolutionized the treatment of various cancers and have shown a great efficacy in inducing antitumor immunity. Cancer immunotherapy in the form of adoptive cell transfer (ACT) have also been developed to eradicate tumor cells in a specific and effective manner, and it includes the administration of autologous tumor-infiltrating T-cells (TILs), T-cell receptor (TCR)-modified T-cells, or genetically engineered chimeric antigen receptor (CAR)-specific T-cells (CARTs) in cancer patients. Additionally, cancer vaccines and recombinant cytokines can be used as monotherapy or adjuvant therapy. Despite the success of immunotherapies in treating various solid tumors and hematologic malignancies, a significant number of patients do not benefit from these therapies and exhibit limited or no response. Some cancer patients do not respond to immunotherapies as a result of primary or intrinsic tumor resistance, while others respond to immunotherapies but develop resistance over time, referred to as adaptive or acquired tumor resistance. Tumor intrinsic- and extrinsic-mediated mechanisms, including genetic and epigenetic alterations, tumor-mutational loads, overexpression of co-inhibitory immune checkpoints, and elevated levels of suppressive immune cells and cytokines, can lead to a compromised antitumor immunity favoring tumorigenesis and cancer progression. This chapter outlines mechanisms of intrinsic tumor resistance and the emergence of acquired tumor resistance to cancer immunotherapies. Moreover, this chapter describes combined cancer immunotherapies, which may offer a great therapeutic potential to overcome tumor resistance against therapy and improve clinical outcomes in cancer patients. +é(c) 2022 Elsevier Inc. All rights reserved
en
Elsevier
https://www.sciencedirect.com/science/article/pii/B9780128233979000144?via%3Dihub
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Acquired resistance
Adoptive T-cell therapy
Cancer
Epigenetics
Immune checkpoint inhibitor
Immunotherapy
Intrinsic resistance
Therapeutic strategies
Tumor microenvironment
Intrinsic and acquired cancer immunotherapy resistance
Book chapter
463
497
Cancer Immunology and Immunotherapy: Volume 1 of Delivery Strategies and Engineering Technologies in Cancer Immunotherapy
THUMBNAIL
2022-08-27
Saleh_Intrinsic and acquired cancer immunotherapy resistance_manuscript-book chapter.pdf.jpg
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2022-08-27
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Saleh_Intrinsic and acquired cancer immunotherapy resistance_manuscript-book chapter.pdf
Manuscript of book chapter 14
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10033/623190
oai:repository.helmholtz-hzi.de:10033/623190
2022-05-11 01:55:48.023
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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oai:repository.helmholtz-hzi.de:10033/6231912022-06-11T02:16:12Zcom_10033_128109col_10033_128110
Song, Mi Hye
fabbb7dbb98a137601683c3a72f4abb2
300
Gupta, Anupriya
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300
Sasidharan Nair, Varun
d030d15ba1e55368fee185030abb9504
500
Oh, Kwonik
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300
2022-06-10T09:07:10Z
2022-06-10T09:07:10Z
2022-04-25
2022-04-05
Song MH, Gupta A, Sasidharan Nair V, Oh K. CD4+ T cells play an essential role in chronic MC903-induced skin inflammation. Biochem Biophys Res Commun. 2022 Jul 5;612:8-14. doi: 10.1016/j.bbrc.2022.04.106. Epub 2022 Apr 25. PMID: 35500442.
0006291X
0006-291X
10.1016/j.bbrc.2022.04.106
http://hdl.handle.net/10033/623191
10902104
Biochemical and Biophysical Research Communications
2-s2.0-85129377111
SCOPUS_ID:85129377111
S0006291X22006489
MC903 skin inflammation model is one of well-characterized murine models of atopic dermatitis and driven by TSLP-mediated type 2 inflammation. Since it can be prepared simply by repetitive applications of MC903 and shows consistent clinical results, this model has been widely used. However, in contrast to human atopic dermatitis which is chronic and closely related to TH2 cells, MC903 induces inflammations temporarily and even in the absence of T cells. Here, we modified the MC903 treatment schedule and developed a chronic MC903-induced skin inflammation model. Mice were sensitized with a high dose of MC903 and challenged with a low dose of MC903. Prior to challenge, mice were allowed to recover completely from the inflammation which occurred during the sensitization. The challenge of MC903 induced skin swelling and type 2 inflammations more rapidly, which was dependent on CD4+ T cells and IL-33. We expect that our mouse model will be beneficial for studying the late course of atopic dermatitis.
MC903 skin inflammation model is one of well-characterized murine models of atopic dermatitis and driven by TSLP-mediated type 2 inflammation. Since it can be prepared simply by repetitive applications of MC903 and shows consistent clinical results, this model has been widely used. However, in contrast to human atopic dermatitis which is chronic and closely related to TH2 cells, MC903 induces inflammations temporarily and even in the absence of T cells. Here, we modified the MC903 treatment schedule and developed a chronic MC903-induced skin inflammation model. Mice were sensitized with a high dose of MC903 and challenged with a low dose of MC903. Prior to challenge, mice were allowed to recover completely from the inflammation which occurred during the sensitization. The challenge of MC903 induced skin swelling and type 2 inflammations more rapidly, which was dependent on CD4+ T cells and IL-33. We expect that our mouse model will be beneficial for studying the late course of atopic dermatitis.
Keywords: Atopic dermatitis; CD4(+) T cell; Challenge; IL-33; MC903; Sensitization.
Copyright © 2022 Elsevier Inc. All rights reserved.
National Research Foundation of Korea
Elsevier
NRF-221 2021R1F1A1061547
Vol. 6
Attribution-NonCommercial 4.0 International
http://creativecommons.org/licenses/by-nc/4.0/
Atopic dermatitis
CD4 T cell +
Challenge
IL-33
MC903
Sensitization
Animals
Cytokines
Dermatitis, Atopic* / chemically induced
Dermatitis, Atopic* / drug therapy
Disease Models, Animal
Inflammation / chemically induced
Mice
Skin
Th2 Cells
CD4+ T cells play an essential role in chronic MC903-induced skin inflammation
Article
612
8
14
Biochemical and Biophysical Research Communications
THUMBNAIL
2023-04-25
Memory T cells in MC903.pdf.jpg
Memory T cells in MC903.pdf.jpg
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TEXT
2023-04-25
Memory T cells in MC903.pdf.txt
Memory T cells in MC903.pdf.txt
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ORIGINAL
Memory T cells in MC903.pdf
Memory T cells in MC903.pdf
Manuscript
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https://repository.helmholtz-hzi.de/bitstream/10033/623191/1/Memory%20T%20cells%20in%20MC903.pdf
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10033/623191
oai:repository.helmholtz-hzi.de:10033/623191
2022-06-11 02:16:12.246
Helmholtz Zentrum für Infektionsforschung Repository
hzi@openrepository.com
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