2024-03-29T07:56:16Zhttp://repository.helmholtz-hzi.de/oai/requestoai:repository.helmholtz-hzi.de:10033/1281132019-08-30T11:36:32Zcom_10033_128109col_10033_128110
To be or not to be a Treg cell: lineage decisions controlled by epigenetic mechanisms.
Toker, Aras
Huehn, Jochen
Experimental Immunology, Helmholtz Centre for Infection Research, Inhoffenstrasse 7, 38124 Braunschweig, Germany.
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.
2011-04-14T09:34:46Z
2011-04-14T09:34:46Z
2011
Article
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
en
oai:repository.helmholtz-hzi.de:10033/1328502019-08-30T11:37:00Zcom_10033_128109col_10033_128110
Extracellular NAD+ shapes the Foxp3+ regulatory T cell compartment through the ART2-P2X7 pathway.
Hubert, Sandra
Rissiek, Björn
Klages, Katjana
Huehn, Jochen
Sparwasser, Tim
Haag, Friedrich
Koch-Nolte, Friedrich
Boyer, Olivier
Seman, Michel
Adriouch, Sahil
Institut National de la Santé et de la Recherche Medicale, U905, 76183 Rouen, France.
ADP Ribose Transferases
Animals
Apoptosis
Forkhead Transcription Factors
L-Selectin
Mice
Mice, Inbred C57BL
NAD
Phosphatidylserines
Receptors, Purinergic P2X7
Signal Transduction
T-Lymphocytes, Regulatory
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.
2011-06-09T10:50:03Z
2011-06-09T10:50:03Z
2010-11-22
Article
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
en
oai:repository.helmholtz-hzi.de:10033/3053872019-08-30T11:37:44Zcom_10033_128109col_10033_128110
TGF-β Signalling Is Required for CD4(+) T Cell Homeostasis But Dispensable for Regulatory T Cell Function.
Sledzińska, Anna
Hemmers, Saskia
Mair, Florian
Gorka, Oliver
Ruland, Jürgen
Fairbairn, Lynsey
Nissler, Anja
Müller, Werner
Waisman, Ari
Becher, Burkhard
Buch, Thorsten
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
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.
2013-11-14T11:04:02Z
2013-11-14T11:04:02Z
2013-10
Article
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
en
Archived with thanks to PLoS biology
oai:repository.helmholtz-hzi.de:10033/3061682019-08-30T11:37:44Zcom_10033_128109col_10033_128110
Neuroprotective intervention by interferon-γ blockade prevents CD8+ T cell-mediated dendrite and synapse loss.
Kreutzfeldt, Mario
Bergthaler, Andreas
Fernandez, Marylise
Brück, Wolfgang
Steinbach, Karin
Vorm, Mariann
Coras, Roland
Blümcke, Ingmar
Bonilla, Weldy V
Fleige, Anne
Forman, Ruth
Müller, Werner
Becher, Burkhard
Misgeld, Thomas
Kerschensteiner, Martin
Pinschewer, Daniel D
Merkler, Doron
Department of Pathology and Immunology and 2 World Health Organization Collaborating Centre for Vaccine Immunology, University of Geneva, 1211 Geneva, Switzerland.
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
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.
2013-12-03T13:57:21Z
2013-12-03T13:57:21Z
2013-09-23
Article
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
en
Archived with thanks to The Journal of experimental medicine
oai:repository.helmholtz-hzi.de:10033/3229042019-08-30T11:34:48Zcom_10033_128109col_10033_128110
Effector molecules released by Th1 but not Th17 cells drive an M1 response in microglia.
Prajeeth, Chittappen K
Löhr, Kirsten
Floess, Stefan
Zimmermann, Julian
Ulrich, Reiner
Gudi, Viktoria
Beineke, Andreas
Baumgärtner, Wolfgang
Müller, Marcus
Huehn, Jochen
Stangel, Martin
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.
2014-07-14T14:20:28Z
2014-07-14T14:20:28Z
2014-03
Article
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
en
Archived with thanks to Brain, behavior, and immunity
oai:repository.helmholtz-hzi.de:10033/3238062019-08-30T11:35:39Zcom_10033_128109col_10033_128110
Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells.
Weiss, Jonathan M
Bilate, Angelina M
Gobert, Michael
Ding, Yi
Curotto de Lafaille, Maria A
Parkhurst, Christopher N
Xiong, Huizhong
Dolpady, Jayashree
Frey, Alan B
Ruocco, Maria Grazia
Yang, Yi
Floess, Stefan
Huehn, Jochen
Oh, Soyoung
Li, Ming O
Niec, Rachel E
Rudensky, Alexander Y
Dustin, Michael L
Littman, Dan R
Lafaille, Juan J
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
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.
2014-07-25T09:24:02Z
2014-07-25T09:24:02Z
2012-09-24
Article
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
en
Archived with thanks to The Journal of experimental medicine
oai:repository.helmholtz-hzi.de:10033/3250882019-08-30T11:35:39Zcom_10033_128109col_10033_128110
Epigenetic modification of the human CCR6 gene is associated with stable CCR6 expression in T cells.
Steinfelder, Svenja
Floess, Stefan
Engelbert, Dirk
Haeringer, Barbara
Baron, Udo
Rivino, Laura
Steckel, Bodo
Gruetzkau, Andreas
Olek, Sven
Geginat, Jens
Huehn, Jochen
Hamann, Alf
Dept. of experimental immunology, Helmholtz Centre for infection reseach, Inhoffenstr. 7, D38124 Braunschweig, Germany.
Cell Separation
DNA Methylation
Epigenesis, Genetic
Flow Cytometry
Gene Expression
Gene Expression Regulation
Humans
Polymerase Chain Reaction
Receptors, CCR6
T-Lymphocytes
Transfection
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.
2014-08-22T13:02:39Z
2014-08-22T13:02:39Z
2011-03-10
Article
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
en
Archived with thanks to Blood
oai:repository.helmholtz-hzi.de:10033/3337032019-08-30T11:28:23Zcom_10033_128109col_10033_128110
The Treg-specific demethylated region stabilizes Foxp3 expression independently of NF-κB signaling.
Schreiber, Lisa
Pietzsch, Beate
Floess, Stefan
Farah, Carla
Jänsch, Lothar
Schmitz, Ingo
Huehn, Jochen
Department Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
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
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.
2014-11-04T14:44:26Z
2014-11-04T14:44:26Z
2014
Article
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
en
oai:repository.helmholtz-hzi.de:10033/3462052019-08-30T11:37:23Zcom_10033_128109col_10033_128110
CD8+ Foxp3+ T cells share developmental and phenotypic features with classical CD4+ Foxp3+ regulatory T cells but lack potent suppressive activity.
Mayer, Christian T
Floess, Stefan
Baru, Abdul Mannan
Lahl, Katharina
Huehn, Jochen
Sparwasser, Tim
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
"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.
2015-03-05T12:16:49Z
2015-03-05T12:16:49Z
2011-03
Article
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
en
oai:repository.helmholtz-hzi.de:10033/5657742019-08-30T11:28:23Zcom_10033_128109col_10033_128110
Development of a unique epigenetic signature during in vivo Th17 differentiation.
Yang, Bi-Huei
Floess, Stefan
Hagemann, Stefanie
Deyneko, Igor V
Groebe, Lothar
Pezoldt, Joern
Sparwasser, Tim
Lochner, Matthias
Huehn, Jochen
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
Animals
Cell Differentiation
DNA Methylation
Epigenesis, Genetic
Female
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Oligonucleotide Array Sequence Analysis
Th17 Cells
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.
2015-08-10T09:03:06Z
2015-08-10T09:03:06Z
2015-02-18
Article
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
en
oai:repository.helmholtz-hzi.de:10033/6209522019-08-30T11:27:16Zcom_10033_128109col_10033_128110
Limited role of regulatory T cells during acute Theiler virus-induced encephalitis in resistant C57BL/6 mice
Prajeeth, Chittappen K
Beineke, Andreas
Iskandar, Cut D
Gudi, Viktoria
Herder, Vanessa
Gerhauser, Ingo
Haist, Verena
Teich, René
Huehn, Jochen
Baumgärtner, Wolfgang
Stangel, Martin
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.
2017-06-15T10:30:24Z
2017-06-15T10:30:24Z
2014-11-13
2015-09-04T08:23:52Z
Journal Article
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
en
Prajeeth et al.; licensee BioMed Central Ltd.
oai:repository.helmholtz-hzi.de:10033/5935462019-08-30T11:36:32Zcom_10033_128109col_10033_128110
Limited role of regulatory T cells during acute Theiler virus-induced encephalitis in resistant C57BL/6 mice.
Prajeeth, Chittappen K
Beineke, Andreas
Iskandar, Cut Dahlia
Gudi, Viktoria
Herder, Vanessa
Gerhauser, Ingo
Haist, Verena
Teich, René
Huehn, Jochen
Baumgärtner, Wolfgang
Stangel, Martin
Helmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany.
Acute Disease
Animals
Cardiovirus Infections
Disease Resistance
Encephalitis, Viral
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
T-Lymphocytes, Regulatory
Theilovirus
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.
2016-01-15T14:12:36Z
2016-01-15T14:12:36Z
2014
Article
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
en
oai:repository.helmholtz-hzi.de:10033/6004662019-08-30T11:37:44Zcom_10033_128109col_10033_128110
Promiscuous Foxp3-cre activity reveals a differential requirement for CD28 in Foxp3⁺ and Foxp3⁻ T cells.
Franckaert, Dean
Dooley, James
Roos, Evelyne
Floess, Stefan
Huehn, Jochen
Luche, Herve
Fehling, Hans Joerg
Liston, Adrian
Linterman, Michelle A
Schlenner, Susan M
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
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
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.
2016-03-02T11:43:24Z
2016-03-02T11:43:24Z
2015-04
Article
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
en
oai:repository.helmholtz-hzi.de:10033/6091262019-08-30T11:25:11Zcom_10033_128109col_10033_128110
Foxp3(+) T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation.
Yang, B-H
Hagemann, S
Mamareli, P
Lauer, U
Hoffmann, U
Beckstette, M
Föhse, L
Prinz, I
Pezoldt, J
Suerbaum, S
Sparwasser, Tim
Hamann, A
Floess, S
Huehn, J
Lochner, M
Helmholtz Centre for infection research, Inhoffenstr.7, 38124 Braunschweig, Germany.
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.
2016-05-12T09:09:24Z
2016-05-12T09:09:24Z
2016-03
Article
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
en
oai:repository.helmholtz-hzi.de:10033/6200512019-08-30T11:28:51Zcom_10033_128109col_10033_128110
Inhibition of the JAK/STAT Signaling Pathway in Regulatory T Cells Reveals a Very Dynamic Regulation of Foxp3 Expression.
Goldstein, Jérémie D
Burlion, Aude
Zaragoza, Bruno
Sendeyo, Kélhia
Polansky, Julia K
Huehn, Jochen
Piaggio, Eliane
Salomon, Benoit L
Marodon, Gilles
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
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
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.
2016-09-13T07:57:50Z
2016-09-13T07:57:50Z
2016
Article
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
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6206702019-08-30T11:32:16Zcom_10033_128109col_10033_128110
Viral Infection of the Central Nervous System Exacerbates Interleukin-10 Receptor Deficiency-Mediated Colitis in SJL Mice.
Uhde, Ann-Kathrin
Herder, Vanessa
Akram Khan, Muhammad
Ciurkiewicz, Malgorzata
Schaudien, Dirk
Teich, René
Floess, Stefan
Baumgärtner, Wolfgang
Huehn, Jochen
Beineke, Andreas
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
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.
2016-12-15T15:33:36Z
2016-12-15T15:33:36Z
2016
Article
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
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6209582019-08-30T11:26:42Zcom_10033_128109col_10033_128110
Unique properties of thymic antigen-presenting cells promote epigenetic imprinting of alloantigen-specific regulatory T cells.
Garg, Garima
Nikolouli, Eirini
Hardtke-Wolenski, Matthias
Toker, Aras
Ohkura, Naganari
Beckstette, Michael
Miyao, Takahisa
Geffers, Robert
Floess, Stefan
Gerdes, Norbert
Lutgens, Esther
Osterloh, Anke
Hori, Shohei
Sakaguchi, Shimon
Jaeckel, Elmar
Huehn, Jochen
Helmholtz Centre for infection research, Inhoffenstr.7, 38124 Braunschweig, Germany.
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.
2017-06-19T12:24:50Z
2017-06-19T12:24:50Z
2017-05-30
Article
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
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6209782019-08-30T11:36:05Zcom_10033_128109com_10033_620644com_10033_338554col_10033_621787col_10033_128110col_10033_620646
Yersinia pseudotuberculosis supports Th17 differentiation and limits de novo regulatory T cell induction by directly interfering with T cell receptor signaling.
Pasztoi, Maria
Bonifacius, Agnes
Pezoldt, Joern
Kulkarni, Devesha
Niemz, Jana
Yang, Juhao
Teich, René
Hajek, Janina
Pisano, Fabio
Rohde, Manfred
Dersch, Petra
Huehn, Jochen
Helmholtz Centre for infection research, Inhoffenstr.7, 38124 Braunschweig, Germany.
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.
2017-06-23T14:41:00Z
2017-06-23T14:41:00Z
2017-04-04
Article
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
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6210702019-08-30T11:32:17Zcom_10033_128109com_10033_620636col_10033_128110col_10033_620638
Alloantigen-Induced Regulatory T Cells Generated in Presence of Vitamin C Display Enhanced Stability of Foxp3 Expression and Promote Skin Allograft Acceptance.
Nikolouli, Eirini
Hardtke-Wolenski, Matthias
Hapke, Martin
Beckstette, Michael
Geffers, Robert
Floess, Stefan
Jaeckel, Elmar
Huehn, Jochen
Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany.
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.
2017-08-22T13:53:21Z
2017-08-22T13:53:21Z
2017
Article
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
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6210822019-08-30T11:36:33Zcom_10033_128109com_10033_620591col_10033_128110col_10033_620599
Activated protein C protects from GvHD via PAR2/PAR3 signalling in regulatory T-cells.
Ranjan, Satish
Goihl, Alexander
Kohli, Shrey
Gadi, Ihsan
Pierau, Mandy
Shahzad, Khurrum
Gupta, Dheerendra
Bock, Fabian
Wang, Hongjie
Shaikh, Haroon
Kähne, Thilo
Reinhold, Dirk
Bank, Ute
Zenclussen, Ana C
Niemz, Jana
Schnöder, Tina M
Brunner-Weinzierl, Monika
Fischer, Thomas
Kalinski, Thomas
Schraven, Burkhart
Luft, Thomas
Huehn, Jochen
Naumann, Michael
Heidel, Florian H
Isermann, Berend
Helmholtz Centre for infection research GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
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.
2017-08-31T13:10:31Z
2017-08-31T13:10:31Z
2017-08-21
Article
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
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6210852019-08-30T11:37:00Zcom_10033_128109col_10033_128110
Helicobacter pylori and its secreted immunomodulator VacA protect against anaphylaxis in experimental models of food allergy.
Kyburz, Andreas
Urban, Sabine
Altobelli, Aleksandra
Floess, Stefan
Huehn, Jochen
Cover, Timothy L
Müller, Anne
Helmholtz Centre for infection research GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
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.
2017-09-01T12:44:31Z
2017-09-01T12:44:31Z
2017-08-12
Article
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
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6211132019-08-30T11:34:22Zcom_10033_128109com_10033_338554col_10033_621787col_10033_128110
Mesenteric lymph node stromal cell-derived extracellular vesicles contribute to peripheral de novo induction of Foxp3(+) regulatory T cells.
Pasztoi, Maria
Pezoldt, Joern
Beckstette, Michael
Lipps, Christoph
Wirth, Dagmar
Rohde, M
Paloczi, Krisztina
Buzas, Edit Iren
Huehn, Jochen
Helmholtz Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
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.
2017-09-19T13:06:36Z
2017-09-19T13:06:36Z
2017-08-18
Article
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
en
info:eu-repo/grantAgreement/EC/H2020/656319
openAccess
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6211192019-08-30T11:36:04Zcom_10033_128109col_10033_128110
Epigenetic orchestration of thymic Treg cell development.
Beyer, Marc
Huehn, Jochen
Helmholtz Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2017-09-25T14:09:11Z
2017-09-25T14:09:11Z
2017-01-19
Article
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/
oai:repository.helmholtz-hzi.de:10033/6211262019-08-30T11:32:17Zcom_10033_620591com_10033_128109com_10033_311308col_10033_620725col_10033_128110col_10033_620721
TCR signalling network organization at the immunological synapses of murine regulatory T cells.
van Ham, Marco
Teich, René
Philipsen, Lars
Niemz, Jana
Amsberg, Nicole
Wissing, Josef
Nimtz, Manfred
Gröbe, Lothar
Kliche, Stefanie
Thiel, Nadine
Klawonn, Frank
Hubo, Mario
Jonuleit, Helmut
Reichardt, Peter
Müller, Andreas J
Huehn, Jochen
Jänsch, Lothar
Helmholtz-Zetrum für Infektionsforschung GmbH, Inhoffenstr.7, 38124 Braunschweig, Germany.
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.
2017-09-28T12:14:50Z
2017-09-28T12:14:50Z
2017-08-17
Article
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
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6211612019-08-30T11:28:51Zcom_10033_128109col_10033_128110
Effectors of Th1 and Th17 cells act on astrocytes and augment their neuroinflammatory properties.
Prajeeth, Chittappen K
Kronisch, Julius
Khorooshi, Reza
Knier, Benjamin
Toft-Hansen, Henrik
Gudi, Viktoria
Floess, Stefan
Huehn, Jochen
Owens, Trevor
Korn, Thomas
Stangel, Martin
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
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.
2017-11-06T14:31:09Z
2017-11-06T14:31:09Z
2017-10-16
Article
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
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6211812019-08-30T11:37:00Zcom_10033_128109col_10033_128110
Gut memories do not fade: epigenetic regulation of lasting gut homing receptor expression in CD4(+) memory T cells.
Szilagyi, B A
Triebus, J
Kressler, C
de Almeida, M
Tierling, S
Durek, P
Mardahl, M
Szilagyi, A
Floess, S
Huehn, Jochen
Syrbe, U
Walter, J
Polansky, J K
Hamann, A
Helmholtz-Zentrum für Infektionsforschhung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
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.
2017-11-21T14:18:04Z
2017-11-21T14:18:04Z
2017-11
Article
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
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6212242019-08-30T11:26:42Zcom_10033_128109com_10033_620644com_10033_620626col_10033_128110col_10033_620646col_10033_620629
Impact of CCR7 on T-Cell Response and Susceptibility to Yersinia pseudotuberculosis Infection.
Pezoldt, Joern
Pisano, Fabio
Heine, Wiebke
Pasztoi, Maria
Rosenheinrich, Maik
Nuss, Aaron M
Pils, Marina C
Prinz, Immo
Förster, Reinhold
Huehn, Jochen
Dersch, Petra
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr.7, 38124 Braunschweig, Germany.
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
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.
2018-01-04T10:58:34Z
2018-01-04T10:58:34Z
2017-09-15
Article
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
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6212902019-08-30T11:37:00Zcom_10033_128109col_10033_128110
Polymicrobial sepsis and non-specific immunization induce adaptive immunosuppression to a similar degree.
Schmoeckel, Katrin
Mrochen, Daniel M
Hühn, Jochen
Pötschke, Christian
Bröker, Barbara M
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
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.
2018-02-21T11:53:15Z
2018-02-21T11:53:15Z
2018
Article
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
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6213322019-08-30T11:29:17Zcom_10033_128109com_10033_620644com_10033_311308col_10033_128110col_10033_620646col_10033_620561
The invasin D protein fromYersinia pseudotuberculosisselectively binds the Fab region of host antibodies and affects colonization of the intestine.
Sadana, Pooja
Geyer, Rebecca
Pezoldt, Joern
Helmsing, Saskia
Huehn, Jochen
Hust, Michael
Dersch, Petra
Scrima, Andrea
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
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.
2018-03-23T15:04:02Z
2018-03-23T15:04:02Z
2018-03-13
Article
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
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6213682019-08-30T11:37:44Zcom_10033_128109col_10033_128110
Intact interleukin-10 receptor signaling protects from hippocampal damage elicited by experimental neurotropic virus infection of SJL mice.
Uhde, Ann-Kathrin
Ciurkiewicz, Malgorzata
Herder, Vanessa
Khan, Muhammad Akram
Hensel, Niko
Claus, Peter
Beckstette, Michael
Teich, René
Floess, Stefan
Baumgärtner, Wolfgang
Jung, Klaus
Huehn, Jochen
Beineke, Andreas
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
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.
2018-05-09T12:14:35Z
2018-05-09T12:14:35Z
2018-04-17
Article
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
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
oai:repository.helmholtz-hzi.de:10033/6213752019-08-30T11:36:27Zcom_10033_128109col_10033_128110
Regulation of neuroinflammatory properties of glial cells by T cell effector molecules.
Prajeeth, Chittappen K
Huehn, Jochen
Stangel, Martin
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
2018-05-18T12:51:09Z
2018-05-18T12:51:09Z
2018-02
Article
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/
oai:repository.helmholtz-hzi.de:10033/6215262019-08-30T11:29:11Zcom_10033_128109col_10033_128110
Effectors of Th1 and Th17 cells act on astrocytes and augment their neuroinflammatory properties.
Prajeeth, Chittappen K
Kronisch, Julius
Khorooshi, Reza
Knier, Benjamin
Toft-Hansen, Henrik
Gudi, Viktoria
Floess, Stefan
Huehn, Jochen
Owens, Trevor
Korn, Thomas
Stangel, Martin
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Astrocytes
Th1
Th17
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.
2018-10-30T15:25:03Z
2018-10-30T15:25:03Z
2017-10-16
Article
1742-2094
29037246
10.1186/s12974-017-0978-3
http://hdl.handle.net/10033/621526
Attribution-NonCommercial-ShareAlike 3.0 United States
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Journal of neuroinflammation
oai:repository.helmholtz-hzi.de:10033/6215332019-08-30T11:29:40Zcom_10033_128109com_10033_620659col_10033_128110col_10033_620660
IFN-γ Producing Th1 Cells Induce Different Transcriptional Profiles in Microglia and Astrocytes.
Prajeeth, Chittappen K
Dittrich-Breiholz, Oliver
Talbot, Steven R
Robert, Philippe A
Huehn, Jochen
Stangel, Martin
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany.
Th1 cells
astrocytes
cytokines
interferon-γ
microglia
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
2018-11-02T11:50:11Z
2018-11-02T11:50:11Z
2018-01-01
Article
1662-5102
30364000
10.3389/fncel.2018.00352
http://hdl.handle.net/10033/621533
Attribution-NonCommercial-ShareAlike 3.0 United States
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Frontiers in cellular neuroscience
oai:repository.helmholtz-hzi.de:10033/6216962019-08-30T11:32:40Zcom_10033_128109col_10033_128110
Blimp1 Prevents Methylation of Foxp3 and Loss of Regulatory T Cell Identity at Sites of Inflammation.
Garg, Garima
Muschaweckh, Andreas
Moreno, Helena
Vasanthakumar, Ajithkumar
Floess, Stefan
Lepennetier, Gildas
Oellinger, Rupert
Zhan, Yifan
Regen, Tommy
Hiltensperger, Michael
Peter, Christian
Aly, Lilian
Knier, Benjamin
Palam, Lakshmi Reddy
Kapur, Reuben
Kaplan, Mark H
Waisman, Ari
Rad, Roland
Schotta, Gunnar
Huehn, Jochen
Kallies, Axel
Korn, Thomas
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Blimp1
CNS
CNS2
DNA methyltransferases
Foxp3
Interleukin-6
epigenetic regulation
inflammation
regulatory T cells
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.
2019-02-19T12:39:26Z
2019-02-19T12:39:26Z
2019-02-12
Article
2211-1247
30759395
10.1016/j.celrep.2019.01.070
http://hdl.handle.net/10033/621696
Cell Reports
info:eu-repo/grantAgreement/ERC/CoG 647215
openAccess
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Elsevier (Cell Press)
Cell reports
oai:repository.helmholtz-hzi.de:10033/6217192019-08-30T11:35:12Zcom_10033_128109com_10033_620644col_10033_128110col_10033_620646
Yersinia Pseudotuberculosis Modulates Regulatory T Cell Stability via Injection of Yersinia Outer Proteins in a Type III Secretion System-Dependent Manner.
Elfiky, Ahmed
Bonifacius, Agnes
Pezoldt, Joern
Pasztoi, Maria
Chaoprasid, Paweena
Sadana, Pooja
El-Sherbeeny, Nagla
Hagras, Magda
Scrima, Andrea
Dersch, Petra
Huehn, Jochen
HZI, Helmholtz Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig Germany.
Foxp3
Yersinia outer proteins
Yersinia pseudotuberculosis
cytotoxic necrotizing factor y
invasins
regulatory T cells
Adaptive immunity is essentially required to control acute infection with enteropathogenic
2019-03-08T10:27:05Z
2019-03-08T10:27:05Z
2018-12-23
Article
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
en
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Akadémiai Kiadó
European journal of microbiology & immunology
oai:repository.helmholtz-hzi.de:10033/6217312019-08-30T11:33:04Zcom_10033_128109com_10033_311624com_10033_6839col_10033_128110col_10033_311625
miR-181a/b-1 controls thymic selection of Treg cells and tunes their suppressive capacity.
Łyszkiewicz, Marcin
Winter, Samantha J
Witzlau, Katrin
Föhse, Lisa
Brownlie, Rebecca
Puchałka, Jacek
Verheyden, Nikita A
Kunze-Schumacher, Heike
Imelmann, Esther
Blume, Jonas
Raha, Solaiman
Sekiya, Takashi
Yoshimura, Akihiko
Frueh, Jochen T
Ullrich, Evelyn
Huehn, Jochen
Weiss, Siegfried
Gutierrez, Maximiliano G
Prinz, Immo
Zamoyska, Rose
Ziętara, Natalia
Krueger, Andreas
HZI, Helmholtz Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7, 38124 Braunschweig Germany.
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.
2019-03-28T12:18:39Z
2019-03-28T12:18:39Z
2019-03-01
Article
1545-7885
30856173
10.1371/journal.pbio.2006716
http://hdl.handle.net/10033/621731
PLOS Biology
en
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
PLOS
PLoS biology
oai:repository.helmholtz-hzi.de:10033/6218632019-07-13T02:26:12Zcom_10033_128109col_10033_128110
Microbiome Dependent Regulation of T and Th17 Cells in Mucosa.
Pandiyan, Pushpa
Bhaskaran, Natarajan
Zou, Mangge
Schneider, Elizabeth
Jayaraman, Sangeetha
Huehn, Jochen
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Th17
Treg
antibiotics
inflammation
microbiome
mucosa
mucosal immunity
resident microbes
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.
2019-07-12T12:22:27Z
2019-07-12T12:22:27Z
2019-01-01
Article
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
en
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Frontiers
Frontiers in immunology
oai:repository.helmholtz-hzi.de:10033/6218742019-08-30T11:26:40Zcom_10033_128109col_10033_128110
Microbiome Dependent Regulation of Tregs and Th17 Cells in Mucosa.
Pandiyan, Pushpa
Bhaskaran, Natarajan
Zou, Mangge
Schneider, Elizabeth
Jayaraman, Sangeetha
Huehn, Jochen
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Th17
Treg
antibiotics
inflammation
microbiome
mucosa
mucosal immunity
resident microbes
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.
2019-07-15T09:51:16Z
2019-07-15T09:51:16Z
2019-01-01
Article
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
en
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Frontiers
Frontiers in immunology
oai:repository.helmholtz-hzi.de:10033/6219112019-08-30T11:26:41Zcom_10033_128109col_10033_621829col_10033_128110
Generation of Foxp3CD25 Regulatory T-Cell Precursors Requires c-Rel and IκB.
Schuster, Marc
Plaza-Sirvent, Carlos
Visekruna, Alexander
Huehn, Jochen
Schmitz, Ingo
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
NF-κB
cell differentiation
common γ-chain cytokines
regulatory T cell
thymus
transcription factor
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.
2019-08-20T13:39:56Z
2019-08-20T13:39:56Z
2019-01-01
Article
1664-3224
31354726
10.3389/fimmu.2019.01583
http://hdl.handle.net/10033/621911
Frontiers in Immunology
en
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Frontiers
Frontiers in immunology
oai:repository.helmholtz-hzi.de:10033/6220092019-11-08T02:20:50Zcom_10033_128109col_10033_128110
Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition).
Cossarizza, Andrea
Chang, Hyun-Dong
Radbruch, Andreas
Acs, Andreas
Adam, Dieter
Adam-Klages, Sabine
Agace, William W
Aghaeepour, Nima
Akdis, Mübeccel
Allez, Matthieu
Almeida, Larissa Nogueira
Alvisi, Giorgia
Anderson, Graham
Andrä, Immanuel
Annunziato, Francesco
Anselmo, Achille
Bacher, Petra
Baldari, Cosima T
Bari, Sudipto
Barnaba, Vincenzo
Barros-Martins, Joana
Battistini, Luca
Bauer, Wolfgang
Baumgart, Sabine
Baumgarth, Nicole
Baumjohann, Dirk
Baying, Bianka
Bebawy, Mary
Becher, Burkhard
Beisker, Wolfgang
Benes, Vladimir
Beyaert, Rudi
Blanco, Alfonso
Boardman, Dominic A
Bogdan, Christian
Borger, Jessica G
Borsellino, Giovanna
Boulais, Philip E
Bradford, Jolene A
Brenner, Dirk
Brinkman, Ryan R
Brooks, Anna E S
Busch, Dirk H
Büscher, Martin
Bushnell, Timothy P
Calzetti, Federica
Cameron, Garth
Cammarata, Ilenia
Cao, Xuetao
Cardell, Susanna L
Casola, Stefano
Cassatella, Marco A
Cavani, Andrea
Celada, Antonio
Chatenoud, Lucienne
Chattopadhyay, Pratip K
Chow, Sue
Christakou, Eleni
Čičin-Šain, Luka
Clerici, Mario
Colombo, Federico S
Cook, Laura
Cooke, Anne
Cooper, Andrea M
Corbett, Alexandra J
Cosma, Antonio
Cosmi, Lorenzo
Coulie, Pierre G
Cumano, Ana
Cvetkovic, Ljiljana
Dang, Van Duc
Dang-Heine, Chantip
Davey, Martin S
Davies, Derek
De Biasi, Sara
Del Zotto, Genny
Dela Cruz, Gelo Victoriano
Delacher, Michael
Della Bella, Silvia
Dellabona, Paolo
Deniz, Günnur
Dessing, Mark
Di Santo, James P
Diefenbach, Andreas
Dieli, Francesco
Dolf, Andreas
Dörner, Thomas
Dress, Regine J
Dudziak, Diana
Dustin, Michael
Dutertre, Charles-Antoine
Ebner, Friederike
Eckle, Sidonia B G
Edinger, Matthias
Eede, Pascale
Ehrhardt, Götz R A
Eich, Marcus
Engel, Pablo
Engelhardt, Britta
Erdei, Anna
Esser, Charlotte
Everts, Bart
Evrard, Maximilien
Falk, Christine S
Fehniger, Todd A
Felipo-Benavent, Mar
Ferry, Helen
Feuerer, Markus
Filby, Andrew
Filkor, Kata
Fillatreau, Simon
Follo, Marie
Förster, Irmgard
Foster, John
Foulds, Gemma A
Frehse, Britta
Frenette, Paul S
Frischbutter, Stefan
Fritzsche, Wolfgang
Galbraith, David W
Gangaev, Anastasia
Garbi, Natalio
Gaudilliere, Brice
Gazzinelli, Ricardo T
Geginat, Jens
Gerner, Wilhelm
Gherardin, Nicholas A
Ghoreschi, Kamran
Gibellini, Lara
Ginhoux, Florent
Goda, Keisuke
Godfrey, Dale I
Goettlinger, Christoph
González-Navajas, Jose M
Goodyear, Carl S
Gori, Andrea
Grogan, Jane L
Grummitt, Daryl
Grützkau, Andreas
Haftmann, Claudia
Hahn, Jonas
Hammad, Hamida
Hämmerling, Günter
Hansmann, Leo
Hansson, Goran
Harpur, Christopher M
Hartmann, Susanne
Hauser, Andrea
Hauser, Anja E
Haviland, David L
Hedley, David
Hernández, Daniela C
Herrera, Guadalupe
Herrmann, Martin
Hess, Christoph
Höfer, Thomas
Hoffmann, Petra
Hogquist, Kristin
Holland, Tristan
Höllt, Thomas
Holmdahl, Rikard
Hombrink, Pleun
Houston, Jessica P
Hoyer, Bimba F
Huang, Bo
Huang, Fang-Ping
Huber, Johanna E
Huehn, Jochen
Hundemer, Michael
Hunter, Christopher A
Hwang, William Y K
Iannone, Anna
Ingelfinger, Florian
Ivison, Sabine M
Jäck, Hans-Martin
Jani, Peter K
Jávega, Beatriz
Jonjic, Stipan
Kaiser, Toralf
Kalina, Tomas
Kamradt, Thomas
Kaufmann, Stefan H E
Keller, Baerbel
Ketelaars, Steven L C
Khalilnezhad, Ahad
Khan, Srijit
Kisielow, Jan
Klenerman, Paul
Knopf, Jasmin
Koay, Hui-Fern
Kobow, Katja
Kolls, Jay K
Kong, Wan Ting
Kopf, Manfred
Korn, Thomas
Kriegsmann, Katharina
Kristyanto, Hendy
Kroneis, Thomas
Krueger, Andreas
Kühne, Jenny
Kukat, Christian
Kunkel, Désirée
Kunze-Schumacher, Heike
Kurosaki, Tomohiro
Kurts, Christian
Kvistborg, Pia
Kwok, Immanuel
Landry, Jonathan
Lantz, Olivier
Lanuti, Paola
LaRosa, Francesca
Lehuen, Agnès
LeibundGut-Landmann, Salomé
Leipold, Michael D
Leung, Leslie Y T
Levings, Megan K
Lino, Andreia C
Liotta, Francesco
Litwin, Virginia
Liu, Yanling
Ljunggren, Hans-Gustaf
Lohoff, Michael
Lombardi, Giovanna
Lopez, Lilly
López-Botet, Miguel
Lovett-Racke, Amy E
Lubberts, Erik
Luche, Herve
Ludewig, Burkhard
Lugli, Enrico
Lunemann, Sebastian
Maecker, Holden T
Maggi, Laura
Maguire, Orla
Mair, Florian
Mair, Kerstin H
Mantovani, Alberto
Manz, Rudolf A
Marshall, Aaron J
Martínez-Romero, Alicia
Martrus, Glòria
Marventano, Ivana
Maslinski, Wlodzimierz
Matarese, Giuseppe
Mattioli, Anna Vittoria
Maueröder, Christian
Mazzoni, Alessio
McCluskey, James
McGrath, Mairi
McGuire, Helen M
McInnes, Iain B
Mei, Henrik E
Melchers, Fritz
Melzer, Susanne
Mielenz, Dirk
Miller, Stephen D
Mills, Kingston H G
Minderman, Hans
Mjösberg, Jenny
Moore, Jonni
Moran, Barry
Moretta, Lorenzo
Mosmann, Tim R
Müller, Susann
Multhoff, Gabriele
Muñoz, Luis Enrique
Münz, Christian
Nakayama, Toshinori
Nasi, Milena
Neumann, Katrin
Ng, Lai Guan
Niedobitek, Antonia
Nourshargh, Sussan
Núñez, Gabriel
O'Connor, José-Enrique
Ochel, Aaron
Oja, Anna
Ordonez, Diana
Orfao, Alberto
Orlowski-Oliver, Eva
Ouyang, Wenjun
Oxenius, Annette
Palankar, Raghavendra
Panse, Isabel
Pattanapanyasat, Kovit
Paulsen, Malte
Pavlinic, Dinko
Penter, Livius
Peterson, Pärt
Peth, Christian
Petriz, Jordi
Piancone, Federica
Pickl, Winfried F
Piconese, Silvia
Pinti, Marcello
Pockley, A Graham
Podolska, Malgorzata Justyna
Poon, Zhiyong
Pracht, Katharina
Prinz, Immo
Pucillo, Carlo E M
Quataert, Sally A
Quatrini, Linda
Quinn, Kylie M
Radbruch, Helena
Radstake, Tim R D J
Rahmig, Susann
Rahn, Hans-Peter
Rajwa, Bartek
Ravichandran, Gevitha
Raz, Yotam
Rebhahn, Jonathan A
Recktenwald, Diether
Reimer, Dorothea
Reis E Sousa, Caetano
Remmerswaal, Ester B M
Richter, Lisa
Rico, Laura G
Riddell, Andy
Rieger, Aja M
Robinson, J Paul
Romagnani, Chiara
Rubartelli, Anna
Ruland, Jürgen
Saalmüller, Armin
Saeys, Yvan
Saito, Takashi
Sakaguchi, Shimon
Sala-de-Oyanguren, Francisco
Samstag, Yvonne
Sanderson, Sharon
Sandrock, Inga
Santoni, Angela
Sanz, Ramon Bellmàs
Saresella, Marina
Sautes-Fridman, Catherine
Sawitzki, Birgit
Schadt, Linda
Scheffold, Alexander
Scherer, Hans U
Schiemann, Matthias
Schildberg, Frank A
Schimisky, Esther
Schlitzer, Andreas
Schlosser, Josephine
Schmid, Stephan
Schmitt, Steffen
Schober, Kilian
Schraivogel, Daniel
Schuh, Wolfgang
Schüler, Thomas
Schulte, Reiner
Schulz, Axel Ronald
Schulz, Sebastian R
Scottá, Cristiano
Scott-Algara, Daniel
Sester, David P
Shankey, T Vincent
Silva-Santos, Bruno
Simon, Anna Katharina
Sitnik, Katarzyna M
Sozzani, Silvano
Speiser, Daniel E
Spidlen, Josef
Stahlberg, Anders
Stall, Alan M
Stanley, Natalie
Stark, Regina
Stehle, Christina
Steinmetz, Tobit
Stockinger, Hannes
Takahama, Yousuke
Takeda, Kiyoshi
Tan, Leonard
Tárnok, Attila
Tiegs, Gisa
Toldi, Gergely
Tornack, Julia
Traggiai, Elisabetta
Trebak, Mohamed
Tree, Timothy I M
Trotter, Joe
Trowsdale, John
Tsoumakidou, Maria
Ulrich, Henning
Urbanczyk, Sophia
van de Veen, Willem
van den Broek, Maries
van der Pol, Edwin
Van Gassen, Sofie
Van Isterdael, Gert
van Lier, René A W
Veldhoen, Marc
Vento-Asturias, Salvador
Vieira, Paulo
Voehringer, David
Volk, Hans-Dieter
von Borstel, Anouk
von Volkmann, Konrad
Waisman, Ari
Walker, Rachael V
Wallace, Paul K
Wang, Sa A
Wang, Xin M
Ward, Michael D
Ward-Hartstonge, Kirsten A
Warnatz, Klaus
Warnes, Gary
Warth, Sarah
Waskow, Claudia
Watson, James V
Watzl, Carsten
Wegener, Leonie
Weisenburger, Thomas
Wiedemann, Annika
Wienands, Jürgen
Wilharm, Anneke
Wilkinson, Robert John
Willimsky, Gerald
Wing, James B
Winkelmann, Rieke
Winkler, Thomas H
Wirz, Oliver F
Wong, Alicia
Wurst, Peter
Yang, Jennie H M
Yang, Juhao
Yazdanbakhsh, Maria
Yu, Liping
Yue, Alice
Zhang, Hanlin
Zhao, Yi
Ziegler, Susanne Maria
Zielinski, Christina
Zimmermann, Jakob
Zychlinsky, Arturo
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
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.
2019-11-07T12:24:02Z
2019-11-07T12:24:02Z
2019-10-01
Article
Eur J Immunol. 2019 Oct;49(10):1457-1973. doi: 10.1002/eji.201970107.
1521-4141
31633216
10.1002/eji.201970107
http://hdl.handle.net/10033/622009
European Journal of Immunology
en
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Wiley
European journal of immunology
oai:repository.helmholtz-hzi.de:10033/6220312019-11-27T02:00:58Zcom_10033_128109col_10033_128110
Dynamic Imprinting of the Treg Cell-Specific Epigenetic Signature in Developing Thymic Regulatory T Cells.
Herppich, Susanne
Toker, Aras
Pietzsch, Beate
Kitagawa, Yohko
Ohkura, Naganari
Miyao, Takahisa
Floess, Stefan
Hori, Shohei
Sakaguchi, Shimon
Huehn, Jochen
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Foxp3
IL-2
TSDR
Treg cell
Treg cell precursors
demethylation
epigenetic signature
thymus
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.
2019-11-26T14:32:23Z
2019-11-26T14:32:23Z
2019-01-01
Article
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
en
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Frontiers
Frontiers in immunology
oai:repository.helmholtz-hzi.de:10033/6220742020-01-11T02:14:02Zcom_10033_128109col_10033_128110
The Transcription Factor MAZR/PATZ1 Regulates the Development of FOXP3 Regulatory T Cells.
Andersen, Liisa
Gülich, Alexandra Franziska
Alteneder, Marlis
Preglej, Teresa
Orola, Maria Jonah
Dhele, Narendra
Stolz, Valentina
Schebesta, Alexandra
Hamminger, Patricia
Hladik, Anastasiya
Floess, Stefan
Krausgruber, Thomas
Faux, Thomas
Andrabi, Syed Bilal Ahmad
Huehn, Jochen
Knapp, Sylvia
Sparwasser, Tim
Bock, Christoph
Laiho, Asta
Elo, Laura L
Rasool, Omid
Lahesmaa, Riitta
Sakaguchi, Shinya
Ellmeier, Wilfried
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
DSS-induced colitis
FOXP3
MAZR
PATZ1
T(reg)
regulatory T cells
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.
2020-01-10T14:46:16Z
2020-01-10T14:46:16Z
2019-12-24
Article
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
en
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Elsevier/ Cel Press
Cell reports
oai:repository.helmholtz-hzi.de:10033/6221012020-01-22T02:27:15Zcom_10033_128109com_10033_620636col_10033_128110col_10033_620638
Chimeric antigen receptor-induced BCL11B suppression propagates NK-like cell development.
Maluski, Marcel
Ghosh, Arnab
Herbst, Jessica
Scholl, Vanessa
Baumann, Rolf
Huehn, Jochen
Geffers, Robert
Meyer, Johann
Maul, Holger
Eiz-Vesper, Britta
Krueger, Andreas
Schambach, Axel
van den Brink, Marcel Rm
Sauer, Martin G
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Immunology
Immunotherapy
Leukemias
T cell development
Transplantation
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.
2020-01-21T14:09:11Z
2020-01-21T14:09:11Z
2019-12-02
Article
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
en
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
American Society for Clinical Investigation
The Journal of clinical investigation
oai:repository.helmholtz-hzi.de:10033/6221482020-02-20T02:04:23Zcom_10033_128109col_10033_128110
Recirculating IL-1R2 Tregs fine-tune intrathymic Treg development under inflammatory conditions.
Nikolouli, Eirini
Elfaki, Yassin
Herppich, Susanne
Schelmbauer, Carsten
Delacher, Michael
Falk, Christine
Mufazalov, Ilgiz A
Waisman, Ari
Feuerer, Markus
Huehn, Jochen
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
IL-1 system
Inflammation
Thymus
Treg development
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.
2020-02-19T11:53:05Z
2020-02-19T11:53:05Z
2020-01-27
Article
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
en
info:eu-repo/grantAgreement/EC/H2020/648145
embargoedAccess
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Springer Nature
Cellular & molecular immunology
oai:repository.helmholtz-hzi.de:10033/6221862020-03-11T02:09:21Zcom_10033_128109col_10033_128110
The Transcription Factor MAZR/PATZ1 Regulates the Development of FOXP3 Regulatory T Cells.
Andersen, Liisa
Gülich, Alexandra Franziska
Alteneder, Marlis
Preglej, Teresa
Orola, Maria Jonah
Dhele, Narendra
Stolz, Valentina
Schebesta, Alexandra
Hamminger, Patricia
Hladik, Anastasiya
Floess, Stefan
Krausgruber, Thomas
Faux, Thomas
Andrabi, Syed Bilal Ahmad
Huehn, Jochen
Knapp, Sylvia
Sparwasser, Tim
Bock, Christoph
Laiho, Asta
Elo, Laura L
Rasool, Omid
Lahesmaa, Riitta
Sakaguchi, Shinya
Ellmeier, Wilfried
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
DSS-induced colitis
FOXP3
MAZR
PATZ1
T(reg)
regulatory T cells
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.
2020-03-03T14:53:08Z
2020-03-03T14:53:08Z
2019-12-24
Article
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
en
info:eu-repo/grantAgreement/EC/H2020/677943
openAccess
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Elsevier/Cell Press
Cell reports
oai:repository.helmholtz-hzi.de:10033/6222562020-05-13T01:29:17Zcom_10033_128109col_10033_128110
Vitamin C supports conversion of human γδ T cells into FOXP3-expressing regulatory cells by epigenetic regulation.
Kouakanou, Léonce
Peters, Christian
Sun, Qiwei
Floess, Stefan
Bhat, Jaydeep
Huehn, Jochen
Kabelitz, Dieter
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
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
2020-05-12T09:06:17Z
2020-05-12T09:06:17Z
2020-04-16
Article
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
en
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Nature Publishing Group
10
1
6550
Scientific reports
England
oai:repository.helmholtz-hzi.de:10033/6223052020-06-23T03:31:11Zcom_10033_128109col_10033_128110
Transmaternal Helicobacter pylori exposure reduces allergic airway inflammation in offspring through regulatory T cells.
Kyburz, Andreas
Fallegger, Angela
Zhang, Xiaozhou
Altobelli, Aleksandra
Artola-Boran, Mariela
Borbet, Timothy
Urban, Sabine
Paul, Petra
Münz, Christian
Floess, Stefan
Huehn, Jochen
Cover, Timothy L
Blaser, Martin J
Taube, Christian
Müller, Anne
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Allergic airway inflammation
epigenetic regulation of allergy and asthma
immune regulation
immune tolerance
metagenomics
microbial interventions during pregnancy
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.
2020-06-22T09:50:53Z
2020-06-22T09:50:53Z
2018-09-19
Article
Other
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
en
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592617/
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Elsevier
143
4
1496
1512.e11
The Journal of allergy and clinical immunology
United States
United States
United States
United States
United States
United States
oai:repository.helmholtz-hzi.de:10033/6223142020-06-26T02:39:29Zcom_10033_128109col_10033_128110
Salt generates anti-inflammatory Th17 cells but amplifies their pathogenicity in pro-inflammatory cytokine microenvironments.
Matthias, Julia
Heink, Sylvia
Picard, Felix Sr
Zeiträg, Julia
Kolz, Anna
Chao, Ying-Yin
Soll, Dominik
de Almeida, Gustavo P
Glasmacher, Elke
Jacobsen, Ilse D
Riedel, Thomas
Peters, Anneli
Floess, Stefan
Huehn, Jochen
Baumjohann, Dirk
Huber, Magdalena
Korn, Thomas
Zielinski, Christina E
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Adaptive immunity
Immunology
Inflammation
T cells
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.
2020-06-25T14:18:44Z
2020-06-25T14:18:44Z
2020-06-02
Article
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
en
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
American Society for Clinical Investigation
The Journal of clinical investigation
United States
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
Staphylococcus aureus Alpha-Toxin Limits Type 1 While Fostering Type 3 Immune Responses.
Bonifacius, Agnes
Goldmann, Oliver
Floess, Stefan
Holtfreter, Silva
Robert, Philippe A
Nordengrün, Maria
Kruse, Friederike
Lochner, Matthias
Falk, Christine S
Schmitz, Ingo
Bröker, Barbara M
Medina, Eva
Huehn, Jochen
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
CD4+ T cells
Staphylococcus aureus
alpha-toxin
innate lymphoid cells
γδ T cells
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.
2020-09-10T07:20:07Z
2020-09-10T07:20:07Z
2020-08-07
Article
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
en
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Frontiers
11
1579
Frontiers in immunology
Switzerland
oai:repository.helmholtz-hzi.de:10033/6225402020-11-04T04:36:51Zcom_10033_128109col_10033_128110
Acute neonatal Listeria monocytogenes infection causes long-term, organ-specific changes in immune cell subset composition.
Zou, Mangge
Yang, Juhao
Wiechers, Carolin
Huehn, Jochen
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
immune system
listeria monocytogenes
long-term consequences
neonatal infection
organ-specific
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.
2020-10-27T13:32:21Z
2020-10-27T13:32:21Z
2020-06-19
Article
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
en
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Akadémiai Kiadó
European journal of microbiology & immunology
Hungary
oai:repository.helmholtz-hzi.de:10033/6227482021-02-18T04:37:51Zcom_10033_128109col_10033_128110
Efficient IL-2R signaling differentially affects the stability, function, and composition of the regulatory T-cell pool.
Permanyer, Marc
Bošnjak, Berislav
Glage, Silke
Friedrichsen, Michaela
Floess, Stefan
Huehn, Jochen
Patzer, Gwendolyn E
Odak, Ivan
Eckert, Nadine
Zargari, Razieh
Ospina-Quintero, Laura
Georgiev, Hristo
Förster, Reinhold
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
IL-2R signaling
Regulatory T cells
Treg heterogeneity
scRNA sequencing
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.
2021-02-17T16:34:24Z
2021-02-17T16:34:24Z
2021-01-06
Article
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
en
Attribution-NonCommercial-ShareAlike 4.0 International
http://creativecommons.org/licenses/by-nc-sa/4.0/
Springer Nature
18
2
398
414
Cellular & molecular immunology
China
oai:repository.helmholtz-hzi.de:10033/6228122021-04-01T01:31:51Zcom_10033_128109col_10033_128110
Lymph node stromal cell subsets-Emerging specialists for tailored tissue-specific immune responses.
Zou, Mangge
Wiechers, Carolin
Huehn, Jochen
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Immune regulation
Infection and inflammation
Lymph node
Mucosal micro-environment
Stromal cells
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.
2021-03-31T14:48:31Z
2021-03-31T14:48:31Z
2021-02-25
Article
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
en
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
Elsevier
311
3
151492
International journal of medical microbiology : IJMM
Germany
oai:repository.helmholtz-hzi.de:10033/6228232021-04-08T01:40:59Zcom_10033_128109com_10033_620659com_10033_620591col_10033_128110col_10033_620724col_10033_620660
Influenza A virus-induced thymus atrophy differentially affects dynamics of conventional and regulatory T-cell development in mice.
Elfaki, Yassin
Robert, Philippe A
Binz, Christoph
Falk, Christine S
Bruder, Dunja
Prinz, Immo
Floess, Stefan
Meyer-Hermann, Michael
Huehn, Jochen
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.; BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany.
Foxp3+ Treg cells ⋅ Influenza A virus ⋅ Mathematical modeling ⋅ Ordinary differential equations ⋅ Thymus atrophy
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.
2021-04-07T14:24:38Z
2021-04-07T14:24:38Z
2021-02-26
Article
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
en
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
Wiley-VCH
European journal of immunology
Germany
oai:repository.helmholtz-hzi.de:10033/6228512021-04-30T01:45:10Zcom_10033_128109com_10033_621723col_10033_621724col_10033_128110
Single-cell chromatin accessibility landscape identifies tissue repair program in human regulatory T cells.
Delacher, Michael
Simon, Malte
Sanderink, Lieke
Hotz-Wagenblatt, Agnes
Wuttke, Marina
Schambeck, Kathrin
Schmidleithner, Lisa
Bittner, Sebastian
Pant, Asmita
Ritter, Uwe
Hehlgans, Thomas
Riegel, Dania
Schneider, Verena
Groeber-Becker, Florian Kai
Eigenberger, Andreas
Gebhard, Claudia
Strieder, Nicholas
Fischer, Alexander
Rehli, Michael
Hoffmann, Petra
Edinger, Matthias
Strowig, Till
Huehn, Jochen
Schmidl, Christian
Werner, Jens M
Prantl, Lukas
Brors, Benedikt
Imbusch, Charles D
Feuerer, Markus
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
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.
2021-04-29T07:07:00Z
2021-04-29T07:07:00Z
2021-03-30
Article
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
en
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
Cell Press
54
4
702
720.e17
Immunity
United States
oai:repository.helmholtz-hzi.de:10033/6228592021-05-07T01:42:01Zcom_10033_128109col_10033_128110
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.
Maus, Irena
Klocke, Michael
Derenkó, Jaqueline
Stolze, Yvonne
Beckstette, Michael
Jost, Carsten
Wibberg, Daniel
Blom, Jochen
Henke, Christian
Willenbücher, Katharina
Rumming, Madis
Rademacher, Antje
Pühler, Alfred
Sczyrba, Alexander
Schlüter, Andreas
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Anaerobic digestion
Bioconversion
Biogas
Integrated -omics
Metabolic activity
Metagenome assembled genomes
Methane
Microbial community structure
Polyomics
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.
2021-05-06T15:17:02Z
2021-05-06T15:17:02Z
2020-03-02
Article
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
en
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
BMC
15
1
7
Environmental microbiome
England
oai:repository.helmholtz-hzi.de:10033/6228902021-06-01T01:45:47Zcom_10033_128109com_10033_621723col_10033_621724col_10033_128110
The microbiota is dispensable for the early stages of peripheral regulatory T cell induction within mesenteric lymph nodes.
Wiechers, Carolin
Zou, Mangge
Galvez, Eric
Beckstette, Michael
Ebel, Maria
Strowig, Till
Huehn, Jochen
Pezoldt, Joern
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Microbiota
Peripheral regulatory T cells
Tolerance
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.
2021-05-31T12:18:34Z
2021-05-31T12:18:34Z
2021-03-24
Article
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
en
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
Springer Nature
18
5
1211
1221
Cellular & molecular immunology
China
oai:repository.helmholtz-hzi.de:10033/6229102021-06-25T01:42:23Zcom_10033_128109col_10033_128110
Generation of Sequencing Libraries for Building Immune Cell Methylomes.
Floess, Stefan
Huehn, Jochen
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Epigenetic regulation
Methylome
Sequencing library
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.
2021-06-24T15:34:11Z
2021-06-24T15:34:11Z
2021-04-30
Article
Book chapter
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.)
en
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
Springer Nature
2285
265
276
Methods in molecular biology (Clifton, N.J.)
United States
oai:repository.helmholtz-hzi.de:10033/6229532021-07-23T01:43:30Zcom_10033_128109col_10033_128110
Transcriptome analysis following neurotropic virus infection reveals faulty innate immunity and delayed antigen presentation in mice susceptible to virus-induced demyelination.
Ciurkiewicz, Malgorzata
Floess, Stefan
Beckstette, Michael
Kummerfeld, Maren
Baumgärtner, Wolfgang
Huehn, Jochen
Beineke, Andreas
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Theiler's murine encephalomyelitis virus
antigen presentation
antiviral response
demyelination
innate immune response
mouse model
neurotropic virus
transcriptome analysis
viral encephalitis
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.
2021-07-22T14:22:33Z
2021-07-22T14:22:33Z
2021-07-06
Article
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)
en
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
Wiley & Sons Ltd.
e13000
Brain pathology (Zurich, Switzerland)
Switzerland
oai:repository.helmholtz-hzi.de:10033/6230112021-09-02T02:41:49Zcom_10033_128109com_10033_622921col_10033_128110col_10033_622926
Tbx21 and foxp3 are Epigenetically Stabilized in T-Bet Tregs That Transiently Accumulate in Influenza A Virus-Infected Lungs.
Elfaki, Yassin
Yang, Juhao
Boehme, Julia
Schultz, Kristin
Bruder, Dunja
Falk, Christine S
Huehn, Jochen
Floess, Stefan
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Foxp3
Tbx21
Tregs
inflammation
influenza A virus
lung
methylation
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.
2021-09-01T11:36:54Z
2021-09-01T11:36:54Z
2021-07-14
Article
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
en
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
MDPI
22
14
International journal of molecular sciences
Switzerland
oai:repository.helmholtz-hzi.de:10033/6230172021-09-09T01:53:12Zcom_10033_128109com_10033_620659col_10033_128110col_10033_620660
Germinal Centre Shutdown.
Arulraj, Theinmozhi
Binder, Sebastian C
Robert, Philippe A
Meyer-Hermann, Michael
BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany.; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
B cell lymphoma
antibody responses
chronic germinal centres
ectopic germinal centres
germinal centre shutdown
vaccination
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.
2021-09-08T12:17:09Z
2021-09-08T12:17:09Z
2021-07-07
Article
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
en
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
Frontiers
12
705240
Frontiers in immunology
Switzerland
oai:repository.helmholtz-hzi.de:10033/6230282021-09-15T01:54:16Zcom_10033_128109col_10033_128110
Mesenteric Lymph Node Transplantation in Mice to Study Immune Responses of the Gastrointestinal Tract.
Shaikh, Haroon
Vargas, Juan Gamboa
Mokhtari, Zeinab
Jarick, Katja J
Ulbrich, Maria
Mosca, Josefina Peña
Viera, Estibaliz Arellano
Graf, Caroline
Le, Duc-Dung
Heinze, Katrin G
Büttner-Herold, Maike
Rosenwald, Andreas
Pezoldt, Joern
Huehn, Jochen
Beilhack, Andreas
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
acute graft-versus host disease
alloreactive T cells
lymph node stromal cells
lymph node transplantation
mesenteric lymph node
mouse models
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.
2021-09-14T09:43:47Z
2021-09-14T09:43:47Z
2021-07-26
Article
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
en
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
Frontiers
12
689896
Frontiers in immunology
Switzerland
oai:repository.helmholtz-hzi.de:10033/6231182021-12-14T03:20:36Zcom_10033_128109com_10033_620659col_10033_621771col_10033_128110col_10033_620660
Nitric oxide controls proliferation of Leishmania major by inhibiting the recruitment of permissive host cells.
Formaglio, Pauline
Alabdullah, Mohamad
Siokis, Anastasios
Handschuh, Juliane
Sauerland, Ina
Fu, Yan
Krone, Anna
Gintschel, Patricia
Stettin, Juliane
Heyde, Sandrina
Mohr, Juliane
Philipsen, Lars
Schröder, Anja
Robert, Philippe A
Zhao, Gang
Khailaie, Sahamoddin
Dudeck, Anne
Bertrand, Jessica
Späth, Gerald F
Kahlfuß, Sascha
Bousso, Philippe
Schraven, Burkhart
Huehn, Jochen
Binder, Sebastian
Meyer-Hermann, Michael
Müller, Andreas J
BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38106 Braunschweig, Germany.
2-photon microscopy
Leishmania
biosensor
iNOS
inflammation
intracellular pathogen
monocyte
nitric oxide
phagocyte
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.
2021-12-13T14:09:55Z
2021-12-13T14:09:55Z
2021-10-15
Article
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
en
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
Cell Press
Immunity
United States
oai:repository.helmholtz-hzi.de:10033/6231252021-12-22T01:49:29Zcom_10033_128109col_10033_128110
K18.1 translates T cell receptor signals into thymic regulatory T cell development.
Ruck, Tobias
Bock, Stefanie
Pfeuffer, Steffen
Schroeter, Christina B
Cengiz, Derya
Marciniak, Paul
Lindner, Maren
Herrmann, Alexander
Liebmann, Marie
Kovac, Stjepana
Gola, Lukas
Rolfes, Leoni
Pawlitzki, Marc
Opel, Nils
Hahn, Tim
Dannlowski, Udo
Pap, Thomas
Luessi, Felix
Schreiber, Julian A
Wünsch, Bernhard
Kuhlmann, Tanja
Seebohm, Guiscard
Tackenberg, Björn
Seja, Patricia
Döring, Frank
Wischmeyer, Erhard
Chasan, Achmet Imam
Roth, Johannes
Klotz, Luisa
Meyer Zu Hörste, Gerd
Wiendl, Heinz
Marschall, Tobias
Floess, Stefan
Huehn, Jochen
Budde, Thomas
Bopp, Tobias
Bittner, Stefan
Meuth, Sven G
HZI, Helmholtz Zentrum für Infektionsforschung, GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.
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.
2021-12-21T11:24:25Z
2021-12-21T11:24:25Z
2021-10-26
Article
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
en
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
nATURE Publishing Group
Cell research
England
oai:repository.helmholtz-hzi.de:10033/6231902022-05-11T01:55:48Zcom_10033_128109col_10033_128110
Intrinsic and acquired cancer immunotherapy resistance
Saleh, Reem
Sasidharan Nair, Varun
Toor, Salman M.
Elkord, Eyad
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
Acquired resistance
Adoptive T-cell therapy
Cancer
Epigenetics
Immune checkpoint inhibitor
Immunotherapy
Intrinsic resistance
Therapeutic strategies
Tumor microenvironment
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
2022-05-10T08:52:24Z
2022-05-10T08:52:24Z
2021-08-27
Book chapter
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
en
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/
Elsevier
463
497
Cancer Immunology and Immunotherapy: Volume 1 of Delivery Strategies and Engineering Technologies in Cancer Immunotherapy
oai:repository.helmholtz-hzi.de:10033/6231912022-06-11T02:16:12Zcom_10033_128109col_10033_128110
CD4+ T cells play an essential role in chronic MC903-induced skin inflammation
Song, Mi Hye
Gupta, Anupriya
Sasidharan Nair, Varun
Oh, Kwonik
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
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
2022-06-10T09:07:10Z
2022-06-10T09:07:10Z
2022-04-25
2022-04-05
Article
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
NRF-221 2021R1F1A1061547
Vol. 6
Attribution-NonCommercial 4.0 International
http://creativecommons.org/licenses/by-nc/4.0/
Elsevier
612
8
14
Biochemical and Biophysical Research Communications