2024-03-28T20:22:11Zhttp://repository.helmholtz-hzi.de/oai/requestoai:repository.helmholtz-hzi.de:10033/1281132019-08-30T11:36:32Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Toker, Aras
author
Huehn, Jochen
author
2011
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.
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
To be or not to be a Treg cell: lineage decisions controlled by epigenetic mechanisms.
oai:repository.helmholtz-hzi.de:10033/1328502019-08-30T11:37:00Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Hubert, Sandra
author
Rissiek, Björn
author
Klages, Katjana
author
Huehn, Jochen
author
Sparwasser, Tim
author
Haag, Friedrich
author
Koch-Nolte, Friedrich
author
Boyer, Olivier
author
Seman, Michel
author
Adriouch, Sahil
author
2010-11-22
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.
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
Extracellular NAD+ shapes the Foxp3+ regulatory T cell compartment through the ART2-P2X7 pathway.
oai:repository.helmholtz-hzi.de:10033/2238322019-08-30T11:29:47Zcom_10033_128109col_10033_621829
00925njm 22002777a 4500
dc
Ewald, F
author
Ueffing, N
author
Brockmann, L
author
Hader, C
author
Telieps, T
author
Schuster, M
author
Schulz, W A
author
Schmitz, I
author
2011
Deregulation of apoptosis is common in cancer and is often caused by overexpression of anti-apoptotic proteins in tumour cells. One important regulator of apoptosis is the cellular FLICE-inhibitory protein (c-FLIP), which is overexpressed, for example, in melanoma and Hodgkin's lymphoma cells. Here, we addressed the question whether deregulated c-FLIP expression in urothelial carcinoma impinges on the ability of death ligands to induce apoptosis. In particular, we investigated the role of the c-FLIP splice variants c-FLIP(long) (c-FLIP(L)) and c-FLIP(short) (c-FLIP(S)), which can have opposing functions. We observed diminished expression of the c-FLIP(L) isoform in urothelial carcinoma tissues as well as in established carcinoma cell lines compared with normal urothelial tissues and cells, whereas c-FLIP(S) was unchanged. Overexpression and RNA interference studies in urothelial cell lines nevertheless demonstrated that c-FLIP remained a crucial factor conferring resistance towards induction of apoptosis by death ligands CD95L and TRAIL. Isoform-specific RNA interference showed c-FLIP(L) to be of particular importance. Thus, urothelial carcinoma cells appear to fine-tune c-FLIP expression to a level sufficient for protection against activation of apoptosis by the extrinsic pathway. Therefore, targeting c-FLIP, and especially the c-FLIP(L) isoform, may facilitate apoptosis-based therapies of bladder cancer in otherwise resistant tumours.
The role of c-FLIP splice variants in urothelial tumours. 2011, 2:e245 Cell Death Dis
2041-4889
22190004
10.1038/cddis.2011.131
http://hdl.handle.net/10033/223832
Cell death & disease
The role of c-FLIP splice variants in urothelial tumours.
oai:repository.helmholtz-hzi.de:10033/2885802019-08-30T11:29:47Zcom_10033_128109col_10033_621829
00925njm 22002777a 4500
dc
Schuster, Marc
author
Annemann, Michaela
author
Plaza-Sirvent, Carlos
author
Schmitz, Ingo
author
2013
Nuclear factor κB (NF-κB) controls a multitude of physiological processes such as cell differentiation, cytokine expression, survival and proliferation. Since NF-κB governs embryogenesis, tissue homeostasis and the functions of innate and adaptive immune cells it represents one of the most important and versatile signaling networks known. Its activity is regulated via the inhibitors of NF-κB signaling, the IκB proteins. Classical IκBs, like the prototypical protein IκBα, sequester NF-κB transcription factors in the cytoplasm by masking of their nuclear localization signals (NLS). Thus, binding of NF-κB to the DNA is inhibited. The accessibility of the NLS is controlled via the degradation of IκBα. Phosphorylation of the conserved serine residues 32 and 36 leads to polyubiquitination and subsequent proteasomal degradation. This process marks the central event of canonical NF-κB activation. Once their NLS is accessible, NF-κB transcription factors translocate into the nucleus, bind to the DNA and regulate the transcription of their respective target genes. Several studies described a distinct group of atypical IκB proteins, referred to as the BCL-3 subfamily. Those atypical IκBs show entirely different sub-cellular localizations, activation kinetics and an unexpected functional diversity. First of all, their interaction with NF-κB transcription factors takes place in the nucleus in contrast to classical IκBs, whose binding to NF-κB predominantly occurs in the cytoplasm. Secondly, atypical IκBs are strongly induced after NF-κB activation, for example by LPS and IL-1β stimulation or triggering of B cell and T cell antigen receptors, but are not degraded in the first place like their conventional relatives. Finally, the interaction of atypical IκBs with DNA-associated NF-κB transcription factors can further enhance or diminish their transcriptional activity. Thus, they do not exclusively act as inhibitors of NF-κB activity. The capacity to modulate NF-κB transcription either positively or negatively, represents their most important and unique mechanistic difference to classical IκBs. Several reports revealed the importance of atypical IκB proteins for immune homeostasis and the severe consequences following their loss of function. This review summarizes insights into the physiological processes regulated by this protein class and the relevance of atypical IκB functioning.
Atypical IκB proteins - nuclear modulators of NF-κB signaling. 2013, 11 (1):23 Cell Commun. Signal
1478-811X
23578005
10.1186/1478-811X-11-23
http://hdl.handle.net/10033/288580
Cell communication and signaling : CCS
Atypical IκB proteins - nuclear modulators of NF-κB signaling.
oai:repository.helmholtz-hzi.de:10033/2931342019-08-30T11:29:47Zcom_10033_128109col_10033_621829
00925njm 22002777a 4500
dc
Keil, E
author
Höcker, R
author
Schuster, M
author
Essmann, F
author
Ueffing, N
author
Hoffman, B
author
Liebermann, D A
author
Pfeffer, K
author
Schulze-Osthoff, K
author
Schmitz, I
author
2013-02
Autophagy is a lysosomal degradation pathway important for cellular homeostasis, mammalian development, cancer and immunity. Many molecular components of autophagy have been identified, but little is known about regulatory mechanisms controlling their effector functions. Here, we show that, in contrast to other p38 MAP kinase activators, the growth arrest and DNA damage 45 beta (Gadd45β)-MAPK/ERK kinase kinase 4 (MEKK4) pathway specifically directs p38 to autophagosomes. This process results in an accumulation of autophagosomes through p38-mediated inhibition of lysosome fusion. Conversely, autophagic flux is increased in p38-deficient fibroblasts and Gadd45β-deficient cells. We further identified the underlying mechanism and demonstrate that phosphorylation of the autophagy regulator autophagy-related (Atg)5 at threonine 75 through p38 is responsible for inhibition of starvation-induced autophagy. Thus, we show for the first time that Atg5 activity is controlled by phosphorylation and, moreover, that the spatial regulation of p38 by Gadd45β/MEKK4 negatively regulates the autophagic process.
Phosphorylation of Atg5 by the Gadd45β-MEKK4-p38 pathway inhibits autophagy. 2013, 20 (2):321-32 Cell Death Differ.
1476-5403
23059785
10.1038/cdd.2012.129
http://hdl.handle.net/10033/293134
Cell death and differentiation
Phosphorylation of Atg5 by the Gadd45β-MEKK4-p38 pathway inhibits autophagy.
oai:repository.helmholtz-hzi.de:10033/2942662019-08-30T11:29:47Zcom_10033_128109col_10033_621829
00925njm 22002777a 4500
dc
Keil, E
author
Höcker, R
author
Schuster, M
author
Essmann, F
author
Ueffing, N
author
Hoffman, B
author
Liebermann, D A
author
Pfeffer, K
author
Schulze-Osthoff, K
author
Schmitz, I
author
2013-02
Autophagy is a lysosomal degradation pathway important for cellular homeostasis, mammalian development, cancer and immunity. Many molecular components of autophagy have been identified, but little is known about regulatory mechanisms controlling their effector functions. Here, we show that, in contrast to other p38 MAP kinase activators, the growth arrest and DNA damage 45 beta (Gadd45β)-MAPK/ERK kinase kinase 4 (MEKK4) pathway specifically directs p38 to autophagosomes. This process results in an accumulation of autophagosomes through p38-mediated inhibition of lysosome fusion. Conversely, autophagic flux is increased in p38-deficient fibroblasts and Gadd45β-deficient cells. We further identified the underlying mechanism and demonstrate that phosphorylation of the autophagy regulator autophagy-related (Atg)5 at threonine 75 through p38 is responsible for inhibition of starvation-induced autophagy. Thus, we show for the first time that Atg5 activity is controlled by phosphorylation and, moreover, that the spatial regulation of p38 by Gadd45β/MEKK4 negatively regulates the autophagic process.
Phosphorylation of Atg5 by the Gadd45β-MEKK4-p38 pathway inhibits autophagy. 2013, 20 (2):321-32 Cell Death Differ.
1476-5403
23059785
10.1038/cdd.2012.129
http://hdl.handle.net/10033/294266
Cell death and differentiation
Phosphorylation of Atg5 by the Gadd45β-MEKK4-p38 pathway inhibits autophagy.
oai:repository.helmholtz-hzi.de:10033/3053872019-08-30T11:37:44Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Sledzińska, Anna
author
Hemmers, Saskia
author
Mair, Florian
author
Gorka, Oliver
author
Ruland, Jürgen
author
Fairbairn, Lynsey
author
Nissler, Anja
author
Müller, Werner
author
Waisman, Ari
author
Becher, Burkhard
author
Buch, Thorsten
author
2013-10
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.
TGF-β Signalling Is Required for CD4(+) T Cell Homeostasis But Dispensable for Regulatory T Cell Function. 2013, 11 (10):e1001674 PLoS Biol.
1545-7885
24115907
10.1371/journal.pbio.1001674
http://hdl.handle.net/10033/305387
PLoS biology
TGF-β Signalling Is Required for CD4(+) T Cell Homeostasis But Dispensable for Regulatory T Cell Function.
oai:repository.helmholtz-hzi.de:10033/3061682019-08-30T11:37:44Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Kreutzfeldt, Mario
author
Bergthaler, Andreas
author
Fernandez, Marylise
author
Brück, Wolfgang
author
Steinbach, Karin
author
Vorm, Mariann
author
Coras, Roland
author
Blümcke, Ingmar
author
Bonilla, Weldy V
author
Fleige, Anne
author
Forman, Ruth
author
Müller, Werner
author
Becher, Burkhard
author
Misgeld, Thomas
author
Kerschensteiner, Martin
author
Pinschewer, Daniel D
author
Merkler, Doron
author
2013-09-23
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.
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
Neuroprotective intervention by interferon-γ blockade prevents CD8+ T cell-mediated dendrite and synapse loss.
oai:repository.helmholtz-hzi.de:10033/3110792019-08-30T11:36:32Zcom_10033_338554com_10033_128109col_10033_621050col_10033_620747
00925njm 22002777a 4500
dc
Trsan, Tihana
author
Busche, Andreas
author
Abram, Maja
author
Wensveen, Felix M
author
Lemmermann, Niels A
author
Arapovic, Maja
author
Babic, Marina
author
Tomic, Adriana
author
Golemac, Mijo
author
Brinkmann, Melanie M
author
Jäger, Wiebke
author
Oxenius, Annette
author
Polic, Bojan
author
Krmpotic, Astrid
author
Messerle, Martin
author
Jonjic, Stipan
author
2013-10-08
Due to a unique pattern of CD8 T-cell response induced by cytomegaloviruses (CMVs), live attenuated CMVs are attractive candidates for vaccine vectors for a number of clinically relevant infections and tumors. NKG2D is one of the most important activating NK cell receptors that plays a role in costimulation of CD8 T cells. Here we demonstrate that the expression of CD8 T-cell epitope of Listeria monocytogenes by a recombinant mouse CMV (MCMV) expressing the NKG2D ligand retinoic acid early-inducible protein 1-gamma (RAE-1γ) dramatically enhanced the effectiveness and longevity of epitope-specific CD8 T-cell response and conferred protection against a subsequent challenge infection with Listeria monocytogenes. Unexpectedly, the attenuated growth in vivo of the CMV vector expressing RAE-1γ and its capacity to enhance specific CD8 T-cell response were preserved even in mice lacking NKG2D, implying additional immune function for RAE-1γ beyond engagement of NKG2D. Thus, vectors expressing RAE-1γ represent a promising approach in the development of CD8 T-cell-based vaccines.
Superior induction and maintenance of protective CD8 T cells in mice infected with mouse cytomegalovirus vector expressing RAE-1γ. 2013, 110 (41):16550-5 Proc. Natl. Acad. Sci. U.S.A.
1091-6490
24052528
10.1073/pnas.1310215110
http://hdl.handle.net/10033/311079
Proceedings of the National Academy of Sciences of the United States of America
Superior induction and maintenance of protective CD8 T cells in mice infected with mouse cytomegalovirus vector expressing RAE-1γ.
oai:repository.helmholtz-hzi.de:10033/3170642019-08-30T11:29:47Zcom_10033_128109col_10033_621829
00925njm 22002777a 4500
dc
Ewald, F
author
Annemann, M
author
Pils, M C
author
Plaza-Sirvent, C
author
Neff, F
author
Erck, C
author
Reinhold, D
author
Schmitz, I
author
2014
Death receptor-mediated apoptosis is a key mechanism for the control of immune responses and dysregulation of this pathway may lead to autoimmunity. Cellular FLICE-inhibitory proteins (c-FLIPs) are known as inhibitors of death receptor-mediated apoptosis. The only short murine c-FLIP splice variant is c-FLIPRaji (c-FLIPR). To investigate the functional role of c-FLIPR in the immune system, we used the vavFLIPR mouse model constitutively expressing murine c-FLIPR in all hematopoietic compartments. Lymphocytes from these mice are protected against CD95-mediated apoptosis and activation-induced cell death. Young vavFLIPR mice display normal lymphocyte compartments, but the lymphocyte populations alter with age. We identified reduced levels of T cells and slightly higher levels of B cells in 1-year-old vavFLIPR mice compared with wild-type (WT) littermates. Moreover, both B and T cells from aged vavFLIPR animals show activated phenotypes. Sera from 1-year-old WT and transgenic animals were analysed for anti-nuclear antibodies. Notably, elevated titres of these autoantibodies were detected in vavFLIPR sera. Furthermore, tissue damage in kidneys and lungs from aged vavFLIPR animals was observed, indicating that vavFLIPR mice develop a systemic lupus erythematosus-like phenotype with age. Taken together, these data suggest that c-FLIPR is an important modulator of apoptosis and enforced expression leads to autoimmunity.
Constitutive expression of murine c-FLIPR causes autoimmunity in aged mice. 2014, 5:e1168 Cell Death Dis
2041-4889
24722293
10.1038/cddis.2014.138
http://hdl.handle.net/10033/317064
Cell death & disease
Constitutive expression of murine c-FLIPR causes autoimmunity in aged mice.
oai:repository.helmholtz-hzi.de:10033/3229042019-08-30T11:34:48Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Prajeeth, Chittappen K
author
Löhr, Kirsten
author
Floess, Stefan
author
Zimmermann, Julian
author
Ulrich, Reiner
author
Gudi, Viktoria
author
Beineke, Andreas
author
Baumgärtner, Wolfgang
author
Müller, Marcus
author
Huehn, Jochen
author
Stangel, Martin
author
2014-03
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.
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
Effector molecules released by Th1 but not Th17 cells drive an M1 response in microglia.
oai:repository.helmholtz-hzi.de:10033/3238062019-08-30T11:35:39Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Weiss, Jonathan M
author
Bilate, Angelina M
author
Gobert, Michael
author
Ding, Yi
author
Curotto de Lafaille, Maria A
author
Parkhurst, Christopher N
author
Xiong, Huizhong
author
Dolpady, Jayashree
author
Frey, Alan B
author
Ruocco, Maria Grazia
author
Yang, Yi
author
Floess, Stefan
author
Huehn, Jochen
author
Oh, Soyoung
author
Li, Ming O
author
Niec, Rachel E
author
Rudensky, Alexander Y
author
Dustin, Michael L
author
Littman, Dan R
author
Lafaille, Juan J
author
2012-09-24
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.
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
Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells.
oai:repository.helmholtz-hzi.de:10033/3250882019-08-30T11:35:39Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Steinfelder, Svenja
author
Floess, Stefan
author
Engelbert, Dirk
author
Haeringer, Barbara
author
Baron, Udo
author
Rivino, Laura
author
Steckel, Bodo
author
Gruetzkau, Andreas
author
Olek, Sven
author
Geginat, Jens
author
Huehn, Jochen
author
Hamann, Alf
author
2011-03-10
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.
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
Epigenetic modification of the human CCR6 gene is associated with stable CCR6 expression in T cells.
oai:repository.helmholtz-hzi.de:10033/3260502019-08-30T11:29:47Zcom_10033_128109col_10033_621829
00925njm 22002777a 4500
dc
Cartron, Michaël L
author
England, Simon R
author
Chiriac, Alina Iulia
author
Josten, Michaele
author
Turner, Robert
author
Rauter, Yvonne
author
Hurd, Alexander
author
Sahl, Hans-Georg
author
Jones, Simon
author
Foster, Simon J
author
2014-07
Human skin fatty acids are a potent aspect of our innate defenses, giving surface protection against potentially invasive organisms. They provide an important parameter in determining the ecology of the skin microflora, and alterations can lead to increased colonization by pathogens such as Staphylococcus aureus. Harnessing skin fatty acids may also give a new avenue of exploration in the generation of control measures against drug-resistant organisms. Despite their importance, the mechanism(s) whereby skin fatty acids kill bacteria has remained largely elusive. Here, we describe an analysis of the bactericidal effects of the major human skin fatty acid cis-6-hexadecenoic acid (C6H) on the human commensal and pathogen S. aureus. Several C6H concentration-dependent mechanisms were found. At high concentrations, C6H swiftly kills cells associated with a general loss of membrane integrity. However, C6H still kills at lower concentrations, acting through disruption of the proton motive force, an increase in membrane fluidity, and its effects on electron transfer. The design of analogues with altered bactericidal effects has begun to determine the structural constraints on activity and paves the way for the rational design of new antistaphylococcal agents.
Bactericidal Activity of the Human Skin Fatty Acid cis-6-Hexadecanoic Acid on Staphylococcus aureus. 2014, 58 (7):3599-609 Antimicrob. Agents Chemother.
1098-6596
24709265
10.1128/AAC.01043-13
http://hdl.handle.net/10033/326050
Antimicrobial agents and chemotherapy
Bactericidal Activity of the Human Skin Fatty Acid cis-6-Hexadecanoic Acid on Staphylococcus aureus.
oai:repository.helmholtz-hzi.de:10033/3337032019-08-30T11:28:23Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Schreiber, Lisa
author
Pietzsch, Beate
author
Floess, Stefan
author
Farah, Carla
author
Jänsch, Lothar
author
Schmitz, Ingo
author
Huehn, Jochen
author
2014
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.
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
The Treg-specific demethylated region stabilizes Foxp3 expression independently of NF-κB signaling.
oai:repository.helmholtz-hzi.de:10033/3379932019-08-30T11:36:33Zcom_10033_338554com_10033_128109col_10033_621050col_10033_620747
00925njm 22002777a 4500
dc
Zhang, Kaiyi
author
Dupont, Aline
author
Torow, Natalia
author
Gohde, Fredrik
author
Leschner, Sara
author
Lienenklaus, Stefan
author
Weiss, Siegfried
author
Brinkmann, Melanie M
author
Kühnel, Mark
author
Hensel, Michael
author
Fulde, Marcus
author
Hornef, Mathias W
author
2014-09
The coordinated action of a variety of virulence factors allows Salmonella enterica to invade epithelial cells and penetrate the mucosal barrier. The influence of the age-dependent maturation of the mucosal barrier for microbial pathogenesis has not been investigated. Here, we analyzed Salmonella infection of neonate mice after oral administration. In contrast to the situation in adult animals, we observed spontaneous colonization, massive invasion of enteroabsorptive cells, intraepithelial proliferation and the formation of large intraepithelial microcolonies. Mucosal translocation was dependent on enterocyte invasion in neonates in the absence of microfold (M) cells. It further resulted in potent innate immune stimulation in the absence of pronounced neutrophil-dominated pathology. Our results identify factors of age-dependent host susceptibility and provide important insight in the early steps of Salmonella infection in vivo. We also present a new small animal model amenable to genetic manipulation of the host for the analysis of the Salmonella enterocyte interaction in vivo.
Age-dependent enterocyte invasion and microcolony formation by Salmonella. 2014, 10 (9):e1004385 PLoS Pathog.
1553-7374
25210785
10.1371/journal.ppat.1004385
http://hdl.handle.net/10033/337993
PLoS pathogens
Age-dependent enterocyte invasion and microcolony formation by Salmonella.
oai:repository.helmholtz-hzi.de:10033/3462052019-08-30T11:37:23Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Mayer, Christian T
author
Floess, Stefan
author
Baru, Abdul Mannan
author
Lahl, Katharina
author
Huehn, Jochen
author
Sparwasser, Tim
author
2011-03
"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.
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
CD8+ Foxp3+ T cells share developmental and phenotypic features with classical CD4+ Foxp3+ regulatory T cells but lack potent suppressive activity.
oai:repository.helmholtz-hzi.de:10033/5657742019-08-30T11:28:23Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Yang, Bi-Huei
author
Floess, Stefan
author
Hagemann, Stefanie
author
Deyneko, Igor V
author
Groebe, Lothar
author
Pezoldt, Joern
author
Sparwasser, Tim
author
Lochner, Matthias
author
Huehn, Jochen
author
2015-02-18
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.
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
Development of a unique epigenetic signature during in vivo Th17 differentiation.
oai:repository.helmholtz-hzi.de:10033/5754182019-08-30T11:29:47Zcom_10033_128109col_10033_621829
00925njm 22002777a 4500
dc
Schmitz, Ingo
author
2013
The vertebrate immune system protects the host against invading pathogens such as viruses, bacteria and parasites. It consists of an innate branch and an adaptive branch that provide immediate and long-lasting protection, respectively. As the immune system is composed of different cell types and distributed throughout the whole body, immune cells need to communicate with each other. Intercellular communication in the immune system is mediated by cytokines, which bind to specific receptors on the cell surface and activate intracellular signalling networks. Growth arrest and DNA damage-inducible 45 (Gadd45) proteins are important components of these intracellular signalling networks. They are induced by a number of cytokines and by bacterial lipopolysaccharide. Within the innate immune system, Gadd45 proteins are crucial for the differentiation of myeloid cells as well as for the function of granulocytes and macrophages. Moreover, Gadd45β regulates autophagy, a catabolic pathway that also degrades intracellular pathogens. Regarding adaptive immunity, Gadd45 proteins are especially well characterized in T cells. For instance, Gadd45β and Gadd45γ regulate cytokine expression and Th1 differentiation, while Gadd45α inhibits p38 kinase activation downstream of the T cell receptor. Due to their many functions in the immune system, deficiency in Gadd45 proteins causes autoimmune diseases and less efficient tumour immunosurveillance.
Gadd45 proteins in immunity. 2013, 793:51-68 Adv. Exp. Med. Biol.
0065-2598
24104473
10.1007/978-1-4614-8289-5_4
http://hdl.handle.net/10033/575418
Advances in experimental medicine and biology
Gadd45 proteins in immunity.
oai:repository.helmholtz-hzi.de:10033/6209522019-08-30T11:27:16Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Prajeeth, Chittappen K
author
Beineke, Andreas
author
Iskandar, Cut D
author
Gudi, Viktoria
author
Herder, Vanessa
author
Gerhauser, Ingo
author
Haist, Verena
author
Teich, René
author
Huehn, Jochen
author
Baumgärtner, Wolfgang
author
Stangel, Martin
author
2014-11-13
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.
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
Limited role of regulatory T cells during acute Theiler virus-induced encephalitis in resistant C57BL/6 mice
oai:repository.helmholtz-hzi.de:10033/5935462019-08-30T11:36:32Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Prajeeth, Chittappen K
author
Beineke, Andreas
author
Iskandar, Cut Dahlia
author
Gudi, Viktoria
author
Herder, Vanessa
author
Gerhauser, Ingo
author
Haist, Verena
author
Teich, René
author
Huehn, Jochen
author
Baumgärtner, Wolfgang
author
Stangel, Martin
author
2014
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.
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
Limited role of regulatory T cells during acute Theiler virus-induced encephalitis in resistant C57BL/6 mice.
oai:repository.helmholtz-hzi.de:10033/6004662019-08-30T11:37:44Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Franckaert, Dean
author
Dooley, James
author
Roos, Evelyne
author
Floess, Stefan
author
Huehn, Jochen
author
Luche, Herve
author
Fehling, Hans Joerg
author
Liston, Adrian
author
Linterman, Michelle A
author
Schlenner, Susan M
author
2015-04
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.
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
Promiscuous Foxp3-cre activity reveals a differential requirement for CD28 in Foxp3⁺ and Foxp3⁻ T cells.
oai:repository.helmholtz-hzi.de:10033/6065922019-08-30T11:33:29Zcom_10033_128109col_10033_621829
00925njm 22002777a 4500
dc
Annemann, Michaela
author
Plaza-Sirvent, Carlos
author
Schuster, Marc
author
Katsoulis-Dimitriou, Konstantinos
author
Kliche, Stefanie
author
Schraven, Burkhart
author
Schmitz, Ingo
author
2016-03
The NF-κB/Rel signalling pathway plays a crucial role in numerous biological processes, including innate and adaptive immunity. NF-κB is a family of transcription factors, whose activity is regulated by the inhibitors of NF-κB (IκB). The IκB proteins comprise two distinct groups, the classical (cytoplasmic) and the atypical (nuclear) IκB proteins. Although the cytoplasmic regulation of NF-κB is well characterised, its nuclear regulation mechanisms remain marginally elucidated. However, work from recent years indicated that nuclear IκBs contribute significantly to the modulation of NF-κB-mediated transcription in the immune system. Here, we discuss the role of the atypical IκB proteins Bcl-3, IκBζ, IκBNS, IκBη and IκBL for the regulation of gene expression and effector functions in immune cells.
Atypical IκB proteins in immune cell differentiation and function. 2016, 171:26-35 Immunol. Lett.
1879-0542
26804211
10.1016/j.imlet.2016.01.006
http://hdl.handle.net/10033/606592
Immunology letters
Atypical IκB proteins in immune cell differentiation and function.
oai:repository.helmholtz-hzi.de:10033/6091262019-08-30T11:25:11Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Yang, B-H
author
Hagemann, S
author
Mamareli, P
author
Lauer, U
author
Hoffmann, U
author
Beckstette, M
author
Föhse, L
author
Prinz, I
author
Pezoldt, J
author
Suerbaum, S
author
Sparwasser, Tim
author
Hamann, A
author
Floess, S
author
Huehn, J
author
Lochner, M
author
2016-03
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.
Foxp3(+) T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation. 2016, 9 (2):444-57 Mucosal Immunol
1935-3456
26307665
10.1038/mi.2015.74
http://hdl.handle.net/10033/609126
Mucosal immunology
Foxp3(+) T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation.
oai:repository.helmholtz-hzi.de:10033/6200512019-08-30T11:28:51Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Goldstein, Jérémie D
author
Burlion, Aude
author
Zaragoza, Bruno
author
Sendeyo, Kélhia
author
Polansky, Julia K
author
Huehn, Jochen
author
Piaggio, Eliane
author
Salomon, Benoit L
author
Marodon, Gilles
author
2016
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.
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
Inhibition of the JAK/STAT Signaling Pathway in Regulatory T Cells Reveals a Very Dynamic Regulation of Foxp3 Expression.
oai:repository.helmholtz-hzi.de:10033/6205482019-08-30T11:26:13Zcom_10033_128109col_10033_621829
00925njm 22002777a 4500
dc
Sosna, Justyna
author
Philipp, Stephan
author
Fuchslocher Chico, Johaiber
author
Saggau, Carina
author
Fritsch, Jürgen
author
Föll, Alexandra
author
Plenge, Johannes
author
Arenz, Christoph
author
Pinkert, Thomas
author
Kalthoff, Holger
author
Trauzold, Anna
author
Schmitz, Ingo
author
Schütze, Stefan
author
Adam, Dieter
author
2016-10-15
Recently, a type of regulated necrosis (RN) called necroptosis was identified to be involved in many pathophysiological processes and emerged as an alternative method to eliminate cancer cells. However, only a few studies have elucidated components of TRAIL-mediated necroptosis useful for anticancer therapy. Therefore, we have compared this type of cell death to tumor necrosis factor (TNF)-mediated necroptosis and found similar signaling through acid and neutral sphingomyelinases, the mitochondrial serine protease HtrA2/Omi, Atg5, and vacuolar H(+)-ATPase. Notably, executive mechanisms of both TRAIL- and TNF-mediated necroptosis are independent of poly(ADP-ribose) polymerase 1 (PARP-1), and depletion of p38α increases the levels of both types of cell death. Moreover, we found differences in signaling between TNF- and TRAIL-mediated necroptosis, e.g., a lack of involvement of ubiquitin carboxyl hydrolase L1 (UCH-L1) and Atg16L1 in executive mechanisms of TRAIL-mediated necroptosis. Furthermore, we discovered indications of an altered involvement of mitochondrial components, since overexpression of the mitochondrial protein Bcl-2 protected Jurkat cells from TRAIL- and TNF-mediated necroptosis, and overexpression of Bcl-XL diminished only TRAIL-induced necroptosis in Colo357 cells. Furthermore, TRAIL does not require receptor internalization and endosome-lysosome acidification to mediate necroptosis. Taken together, pathways described for TRAIL-mediated necroptosis and differences from those for TNF-mediated necroptosis might be unique targets to increase or modify necroptotic signaling and eliminate tumor cells more specifically in future anticancer approaches.
Differences and Similarities in TRAIL- and Tumor Necrosis Factor-Mediated Necroptotic Signaling in Cancer Cells. 2016, 36 (20):2626-44 Mol. Cell. Biol.
1098-5549
27528614
10.1128/MCB.00941-15
http://hdl.handle.net/10033/620548
Molecular and cellular biology
Differences and Similarities in TRAIL- and Tumor Necrosis Factor-Mediated Necroptotic Signaling in Cancer Cells.
oai:repository.helmholtz-hzi.de:10033/6205932019-08-30T11:29:17Zcom_10033_128109col_10033_621829
00925njm 22002777a 4500
dc
Neumann, Yvonne
author
Bruns, Svenja A
author
Rohde, Manfred
author
Prajsnar, Tomasz K
author
Foster, Simon J
author
Schmitz, Ingo
author
2016-11
Autophagy, a catabolic pathway of lysosomal degradation, acts not only as an efficient recycle and survival mechanism during cellular stress, but also as an anti-infective machinery. The human pathogen Staphylococcus aureus (S. aureus) was originally considered solely as an extracellular bacterium, but is now recognized additionally to invade host cells, which might be crucial for persistence. However, the intracellular fate of S. aureus is incompletely understood. Here, we show for the first time induction of selective autophagy by S. aureus infection, its escape from autophagosomes and proliferation in the cytoplasm using live cell imaging. After invasion, S. aureus becomes ubiquitinated and recognized by receptor proteins such as SQSTM1/p62 leading to phagophore recruitment. Yet, S. aureus evades phagophores and prevents further degradation by a MAPK14/p38α MAP kinase-mediated blockade of autophagy. Our study demonstrates a novel bacterial strategy to block autophagy and secure survival inside the host cell.
Intracellular Staphylococcus aureus eludes selective autophagy by activating a host cell kinase. 2016, 12 (11):2069-2084 Autophagy
1554-8627
27629870
10.1080/15548627.2016.1226732
http://hdl.handle.net/10033/620593
Autophagy
Intracellular Staphylococcus aureus eludes selective autophagy by activating a host cell kinase.
oai:repository.helmholtz-hzi.de:10033/6206702019-08-30T11:32:16Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Uhde, Ann-Kathrin
author
Herder, Vanessa
author
Akram Khan, Muhammad
author
Ciurkiewicz, Malgorzata
author
Schaudien, Dirk
author
Teich, René
author
Floess, Stefan
author
Baumgärtner, Wolfgang
author
Huehn, Jochen
author
Beineke, Andreas
author
2016
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.
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
Viral Infection of the Central Nervous System Exacerbates Interleukin-10 Receptor Deficiency-Mediated Colitis in SJL Mice.
oai:repository.helmholtz-hzi.de:10033/6209582019-08-30T11:26:42Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Garg, Garima
author
Nikolouli, Eirini
author
Hardtke-Wolenski, Matthias
author
Toker, Aras
author
Ohkura, Naganari
author
Beckstette, Michael
author
Miyao, Takahisa
author
Geffers, Robert
author
Floess, Stefan
author
Gerdes, Norbert
author
Lutgens, Esther
author
Osterloh, Anke
author
Hori, Shohei
author
Sakaguchi, Shimon
author
Jaeckel, Elmar
author
Huehn, Jochen
author
2017-05-30
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.
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
Unique properties of thymic antigen-presenting cells promote epigenetic imprinting of alloantigen-specific regulatory T cells.
oai:repository.helmholtz-hzi.de:10033/6209782019-08-30T11:36:05Zcom_10033_128109com_10033_620644com_10033_338554col_10033_621787col_10033_128110col_10033_620646
00925njm 22002777a 4500
dc
Pasztoi, Maria
author
Bonifacius, Agnes
author
Pezoldt, Joern
author
Kulkarni, Devesha
author
Niemz, Jana
author
Yang, Juhao
author
Teich, René
author
Hajek, Janina
author
Pisano, Fabio
author
Rohde, Manfred
author
Dersch, Petra
author
Huehn, Jochen
author
2017-04-04
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.
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
Yersinia pseudotuberculosis supports Th17 differentiation and limits de novo regulatory T cell induction by directly interfering with T cell receptor signaling.
oai:repository.helmholtz-hzi.de:10033/6210022019-08-30T11:34:48Zcom_10033_128109col_10033_621829
00925njm 22002777a 4500
dc
Plaza-Sirvent, Carlos
author
Schuster, Marc
author
Neumann, Yvonne
author
Heise, Ulrike
author
Pils, Marina C
author
Schulze-Osthoff, Klaus
author
Schmitz, Ingo
author
2017-01-03
Regulatory T (Treg) cells are critical for the shutdown of immune responses and have emerged as valuable targets of immunotherapies. Treg cells can rapidly proliferate; however, the homeostatic processes that limit excessive Treg cell numbers are poorly understood. Here, we show that, compared to conventional T cells, Treg cells have a high apoptosis rate ex vivo correlating with low c-FLIP expression. Treg-specific deletion of c-FLIP in mice resulted in fatal autoimmune disease of a scurfy-like phenotype characterized by absent peripheral Treg cells, activation of effector cells, multi-organ immune cell infiltration, and premature death. Surprisingly, blocking CD95L did not rescue Treg survival in vivo, suggesting additional survival functions of c-FLIP in Treg cells in addition to its classical role in the inhibition of death receptor signaling. Thus, our data reveal a central role for c-FLIP in Treg cell homeostasis and prevention of autoimmunity.
c-FLIP Expression in Foxp3-Expressing Cells Is Essential for Survival of Regulatory T Cells and Prevention of Autoimmunity. 2017, 18 (1):12-22 Cell Rep
2211-1247
28052242
10.1016/j.celrep.2016.12.022
http://hdl.handle.net/10033/621002
Cell reports
c-FLIP Expression in Foxp3-Expressing Cells Is Essential for Survival of Regulatory T Cells and Prevention of Autoimmunity.
oai:repository.helmholtz-hzi.de:10033/6210702019-08-30T11:32:17Zcom_10033_128109com_10033_620636col_10033_128110col_10033_620638
00925njm 22002777a 4500
dc
Nikolouli, Eirini
author
Hardtke-Wolenski, Matthias
author
Hapke, Martin
author
Beckstette, Michael
author
Geffers, Robert
author
Floess, Stefan
author
Jaeckel, Elmar
author
Huehn, Jochen
author
2017
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.
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
Alloantigen-Induced Regulatory T Cells Generated in Presence of Vitamin C Display Enhanced Stability of Foxp3 Expression and Promote Skin Allograft Acceptance.
oai:repository.helmholtz-hzi.de:10033/6210822019-08-30T11:36:33Zcom_10033_128109com_10033_620591col_10033_128110col_10033_620599
00925njm 22002777a 4500
dc
Ranjan, Satish
author
Goihl, Alexander
author
Kohli, Shrey
author
Gadi, Ihsan
author
Pierau, Mandy
author
Shahzad, Khurrum
author
Gupta, Dheerendra
author
Bock, Fabian
author
Wang, Hongjie
author
Shaikh, Haroon
author
Kähne, Thilo
author
Reinhold, Dirk
author
Bank, Ute
author
Zenclussen, Ana C
author
Niemz, Jana
author
Schnöder, Tina M
author
Brunner-Weinzierl, Monika
author
Fischer, Thomas
author
Kalinski, Thomas
author
Schraven, Burkhart
author
Luft, Thomas
author
Huehn, Jochen
author
Naumann, Michael
author
Heidel, Florian H
author
Isermann, Berend
author
2017-08-21
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.
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
Activated protein C protects from GvHD via PAR2/PAR3 signalling in regulatory T-cells.
oai:repository.helmholtz-hzi.de:10033/6210852019-08-30T11:37:00Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Kyburz, Andreas
author
Urban, Sabine
author
Altobelli, Aleksandra
author
Floess, Stefan
author
Huehn, Jochen
author
Cover, Timothy L
author
Müller, Anne
author
2017-08-12
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.
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
Helicobacter pylori and its secreted immunomodulator VacA protect against anaphylaxis in experimental models of food allergy.
oai:repository.helmholtz-hzi.de:10033/6211002021-07-05T15:12:57Zcom_10033_311308com_10033_128109com_10033_622921col_10033_622922col_10033_621829col_10033_620561
00925njm 22002777a 4500
dc
Chaudhry, M Zeeshan
author
Kasmapour, Bahram
author
Plaza-Sirvent, Carlos
author
Bajagic, Milica
author
Casalegno Garduño, Rosaely
author
Borkner, Lisa
author
Lenac Roviš, Tihana
author
Scrima, Andrea
author
Jonjic, Stipan
author
Schmitz, Ingo
author
Cicin-Sain, Luka
author
2017
Apoptosis is an important defense mechanism mounted by the immune system to control virus replication. Hence, cytomegaloviruses (CMV) evolved and acquired numerous anti-apoptotic genes. The product of the human CMV (HCMV) UL36 gene, pUL36 (also known as vICA), binds to pro-caspase-8, thus inhibiting death-receptor apoptosis and enabling viral replication in differentiated THP-1 cells. In vivo studies of the function of HCMV genes are severely limited due to the strict host specificity of cytomegaloviruses, but CMV orthologues that co-evolved with other species allow the experimental study of CMV biology in vivo. The mouse CMV (MCMV) homolog of the UL36 gene is called M36, and its protein product (pM36) is a functional homolog of vICA that binds to murine caspase-8 and inhibits its activation. M36-deficient MCMV is severely growth impaired in macrophages and in vivo. Here we show that pUL36 binds to the murine pro-caspase-8, and that UL36 expression inhibits death-receptor apoptosis in murine cells and can replace M36 to allow MCMV growth in vitro and in vivo. We generated a chimeric MCMV expressing the UL36 ORF sequence instead of the M36 one. The newly generated MCMV(UL36) inhibited apoptosis in macrophage lines RAW 264.7, J774A.1, and IC-21 and its growth was rescued to wild type levels. Similarly, growth was rescued in vivo in the liver and spleen, but only partially in the salivary glands of BALB/c and C57BL/6 mice. In conclusion, we determined that an immune-evasive HCMV gene is conserved enough to functionally replace its MCMV counterpart and thus allow its study in an in vivo setting. As UL36 and M36 proteins engage the same molecular host target, our newly developed model can facilitate studies of anti-viral compounds targeting pUL36 in vivo.
UL36 Rescues Apoptosis Inhibition and In vivo Replication of a Chimeric MCMV Lacking the M36 Gene. 2017, 7:312 Front Cell Infect Microbiol
2235-2988
28770171
10.3389/fcimb.2017.00312
http://hdl.handle.net/10033/621100
Frontiers in cellular and infection microbiology
UL36 Rescues Apoptosis Inhibition and In vivo Replication of a Chimeric MCMV Lacking the M36 Gene.
oai:repository.helmholtz-hzi.de:10033/6211132019-08-30T11:34:22Zcom_10033_128109com_10033_338554col_10033_621787col_10033_128110
00925njm 22002777a 4500
dc
Pasztoi, Maria
author
Pezoldt, Joern
author
Beckstette, Michael
author
Lipps, Christoph
author
Wirth, Dagmar
author
Rohde, M
author
Paloczi, Krisztina
author
Buzas, Edit Iren
author
Huehn, Jochen
author
2017-08-18
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.
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
Mesenteric lymph node stromal cell-derived extracellular vesicles contribute to peripheral de novo induction of Foxp3(+) regulatory T cells.
oai:repository.helmholtz-hzi.de:10033/6211192019-08-30T11:36:04Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Beyer, Marc
author
Huehn, Jochen
author
2017-01-19
Epigenetic orchestration of thymic Treg cell development. 2017, 18 (2):144-146 Nat. Immunol.
1529-2916
28102221
10.1038/ni.3660
http://hdl.handle.net/10033/621119
Nature immunology
Epigenetic orchestration of thymic Treg cell development.
oai:repository.helmholtz-hzi.de:10033/6211262019-08-30T11:32:17Zcom_10033_620591com_10033_128109com_10033_311308col_10033_620725col_10033_128110col_10033_620721
00925njm 22002777a 4500
dc
van Ham, Marco
author
Teich, René
author
Philipsen, Lars
author
Niemz, Jana
author
Amsberg, Nicole
author
Wissing, Josef
author
Nimtz, Manfred
author
Gröbe, Lothar
author
Kliche, Stefanie
author
Thiel, Nadine
author
Klawonn, Frank
author
Hubo, Mario
author
Jonuleit, Helmut
author
Reichardt, Peter
author
Müller, Andreas J
author
Huehn, Jochen
author
Jänsch, Lothar
author
2017-08-17
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.
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
TCR signalling network organization at the immunological synapses of murine regulatory T cells.
oai:repository.helmholtz-hzi.de:10033/6211612019-08-30T11:28:51Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Prajeeth, Chittappen K
author
Kronisch, Julius
author
Khorooshi, Reza
author
Knier, Benjamin
author
Toft-Hansen, Henrik
author
Gudi, Viktoria
author
Floess, Stefan
author
Huehn, Jochen
author
Owens, Trevor
author
Korn, Thomas
author
Stangel, Martin
author
2017-10-16
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.
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
Effectors of Th1 and Th17 cells act on astrocytes and augment their neuroinflammatory properties.
oai:repository.helmholtz-hzi.de:10033/6211812019-08-30T11:37:00Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Szilagyi, B A
author
Triebus, J
author
Kressler, C
author
de Almeida, M
author
Tierling, S
author
Durek, P
author
Mardahl, M
author
Szilagyi, A
author
Floess, S
author
Huehn, Jochen
author
Syrbe, U
author
Walter, J
author
Polansky, J K
author
Hamann, A
author
2017-11
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.
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
Gut memories do not fade: epigenetic regulation of lasting gut homing receptor expression in CD4(+) memory T cells.
oai:repository.helmholtz-hzi.de:10033/6212042019-08-30T11:26:42Zcom_10033_620659com_10033_620652com_10033_128109col_10033_621829col_10033_620672col_10033_620660
00925njm 22002777a 4500
dc
Zhao, Gang
author
Wirth, Dagmar
author
Schmitz, Ingo
author
Meyer-Hermann, Michael
author
2017-11-08
Physiological insulin secretion exhibits various temporal patterns, the dysregulation of which is involved in diabetes development. We analyzed the impact of first-phase and pulsatile insulin release on glucose and lipid control with various hepatic insulin signaling networks. The mathematical model suggests that atypical protein kinase C (aPKC) undergoes a bistable switch-on and switch-off, under the control of insulin receptor substrate 2 (IRS2). The activation of IRS1 and IRS2 is temporally separated due to the inhibition of IRS1 by aPKC. The model further shows that the timing of aPKC switch-off is delayed by reduced first-phase insulin and reduced amplitude of insulin pulses. Based on these findings, we propose a sequential model of postprandial hepatic control of glucose and lipid by insulin, according to which delayed aPKC switch-off contributes to selective hepatic insulin resistance, which is a long-standing paradox in the field.
A mathematical model of the impact of insulin secretion dynamics on selective hepatic insulin resistance. 2017, 8 (1):1362 Nat Commun
2041-1723
29118381
10.1038/s41467-017-01627-9
http://hdl.handle.net/10033/621204
Nature communications
A mathematical model of the impact of insulin secretion dynamics on selective hepatic insulin resistance.
oai:repository.helmholtz-hzi.de:10033/6212242019-08-30T11:26:42Zcom_10033_128109com_10033_620644com_10033_620626col_10033_128110col_10033_620646col_10033_620629
00925njm 22002777a 4500
dc
Pezoldt, Joern
author
Pisano, Fabio
author
Heine, Wiebke
author
Pasztoi, Maria
author
Rosenheinrich, Maik
author
Nuss, Aaron M
author
Pils, Marina C
author
Prinz, Immo
author
Förster, Reinhold
author
Huehn, Jochen
author
Dersch, Petra
author
2017-09-15
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.
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
Impact of CCR7 on T-Cell Response and Susceptibility to Yersinia pseudotuberculosis Infection.
oai:repository.helmholtz-hzi.de:10033/6212262019-08-30T11:30:58Zcom_10033_128109col_10033_620747
00925njm 22002777a 4500
dc
Babdor, Joel
author
Descamps, Delphyne
author
Adiko, Aimé Cézaire
author
Tohmé, Mira
author
Maschalidi, Sophia
author
Evnouchidou, Irini
author
Vasconcellos, Luiz Ricardo
author
De Luca, Mariacristina
author
Mauvais, Francois-Xavier
author
Garfa-Traore, Meriem
author
Brinkmann, Melanie M
author
Chignard, Michel
author
Manoury, Bénédicte
author
Saveanu, Loredana
author
2017-05
The retention of intracellular Toll-like receptors (TLRs) in the endoplasmic reticulum prevents their activation under basal conditions. TLR9 is activated by sensing ligands in specific endosomal-lysosomal compartments. Here we identified IRAP+ endosomes as major cellular compartments for the early steps of TLR9 activation in dendritic cells (DCs). Both TLR9 and its ligand, the dinucleotide CpG, were present as cargo in IRAP+ endosomes. In the absence of the aminopeptidase IRAP, the trafficking of CpG and TLR9 to lysosomes and signaling via TLR9 were enhanced in DCs and in mice following bacterial infection. IRAP stabilized CpG-containing endosomes by interacting with the actin-nucleation factor FHOD4, which slowed the trafficking of TLR9 toward lysosomes. Thus, endosomal retention of TLR9 via the interaction of IRAP with the actin cytoskeleton is a mechanism that prevents hyper-activation of TLR9 in DCs.
IRAP+ endosomes restrict TLR9 activation and signaling. 2017, 18 (5):509-518 Nat. Immunol.
1529-2916
28319098
10.1038/ni.3711
http://hdl.handle.net/10033/621226
Nature immunology
IRAP+ endosomes restrict TLR9 activation and signaling.
oai:repository.helmholtz-hzi.de:10033/6212902019-08-30T11:37:00Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Schmoeckel, Katrin
author
Mrochen, Daniel M
author
Hühn, Jochen
author
Pötschke, Christian
author
Bröker, Barbara M
author
2018
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.
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
Polymicrobial sepsis and non-specific immunization induce adaptive immunosuppression to a similar degree.
oai:repository.helmholtz-hzi.de:10033/6213322019-08-30T11:29:17Zcom_10033_128109com_10033_620644com_10033_311308col_10033_128110col_10033_620646col_10033_620561
00925njm 22002777a 4500
dc
Sadana, Pooja
author
Geyer, Rebecca
author
Pezoldt, Joern
author
Helmsing, Saskia
author
Huehn, Jochen
author
Hust, Michael
author
Dersch, Petra
author
Scrima, Andrea
author
2018-03-13
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.
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
The invasin D protein fromYersinia pseudotuberculosisselectively binds the Fab region of host antibodies and affects colonization of the intestine.
oai:repository.helmholtz-hzi.de:10033/6213682019-08-30T11:37:44Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Uhde, Ann-Kathrin
author
Ciurkiewicz, Malgorzata
author
Herder, Vanessa
author
Khan, Muhammad Akram
author
Hensel, Niko
author
Claus, Peter
author
Beckstette, Michael
author
Teich, René
author
Floess, Stefan
author
Baumgärtner, Wolfgang
author
Jung, Klaus
author
Huehn, Jochen
author
Beineke, Andreas
author
2018-04-17
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.
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
Intact interleukin-10 receptor signaling protects from hippocampal damage elicited by experimental neurotropic virus infection of SJL mice.
oai:repository.helmholtz-hzi.de:10033/6213752019-08-30T11:36:27Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Prajeeth, Chittappen K
author
Huehn, Jochen
author
Stangel, Martin
author
2018-02
Regulation of neuroinflammatory properties of glial cells by T cell effector molecules. 2018, 13 (2):234-236 Neural Regen Res
1673-5374
29557369
10.4103/1673-5374.226385
http://hdl.handle.net/10033/621375
Neural regeneration research
Regulation of neuroinflammatory properties of glial cells by T cell effector molecules.
oai:repository.helmholtz-hzi.de:10033/6215262019-08-30T11:29:11Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Prajeeth, Chittappen K
author
Kronisch, Julius
author
Khorooshi, Reza
author
Knier, Benjamin
author
Toft-Hansen, Henrik
author
Gudi, Viktoria
author
Floess, Stefan
author
Huehn, Jochen
author
Owens, Trevor
author
Korn, Thomas
author
Stangel, Martin
author
2017-10-16
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.
1742-2094
29037246
10.1186/s12974-017-0978-3
http://hdl.handle.net/10033/621526
Astrocytes
Th1
Th17
Effectors of Th1 and Th17 cells act on astrocytes and augment their neuroinflammatory properties.
oai:repository.helmholtz-hzi.de:10033/6215332019-08-30T11:29:40Zcom_10033_128109com_10033_620659col_10033_128110col_10033_620660
00925njm 22002777a 4500
dc
Prajeeth, Chittappen K
author
Dittrich-Breiholz, Oliver
author
Talbot, Steven R
author
Robert, Philippe A
author
Huehn, Jochen
author
Stangel, Martin
author
2018-01-01
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
1662-5102
30364000
10.3389/fncel.2018.00352
http://hdl.handle.net/10033/621533
Th1 cells
astrocytes
cytokines
interferon-γ
microglia
IFN-γ Producing Th1 Cells Induce Different Transcriptional Profiles in Microglia and Astrocytes.
oai:repository.helmholtz-hzi.de:10033/6216902019-08-30T11:32:39Zcom_10033_620591com_10033_128109col_10033_621829col_10033_620599
00925njm 22002777a 4500
dc
Lowinus, Theresa
author
Heidel, Florian H
author
Bose, Tanima
author
Nimmagadda, Subbaiah Chary
author
Schnöder, Tina
author
Cammann, Clemens
author
Schmitz, Ingo
author
Seifert, Ulrike
author
Fischer, Thomas
author
Schraven, Burkhart
author
Bommhardt, Ursula
author
2019-01-16
Treatment of acute leukemia is challenging and long-lasting remissions are difficult to induce. Innovative therapy approaches aim to complement standard chemotherapy to improve drug efficacy and decrease toxicity. Promising new therapeutic targets in cancer therapy include voltage-gated K We analyzed acute lymphoid (Jurkat, CEM) and myeloid (HL-60, Molm-13, OCI-AML-3) leukemia cell lines and patients' acute leukemic blasts after treatment with either drug alone or the combination of cytarabine and memantine. Patch-clamp analysis was performed to evaluate inhibition of K Our study demonstrates that memantine inhibits K Our study underlines inhibition of K
1478-811X
30651113
10.1186/s12964-018-0317-z
http://hdl.handle.net/10033/621690
Cell Communication and Signaling
Acute leukemia
Cell death
Cytarabine
Memantine
Signaling
Memantine potentiates cytarabine-induced cell death of acute leukemia correlating with inhibition of K1.3 potassium channels, AKT and ERK1/2 signaling.
oai:repository.helmholtz-hzi.de:10033/6216962019-08-30T11:32:40Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Garg, Garima
author
Muschaweckh, Andreas
author
Moreno, Helena
author
Vasanthakumar, Ajithkumar
author
Floess, Stefan
author
Lepennetier, Gildas
author
Oellinger, Rupert
author
Zhan, Yifan
author
Regen, Tommy
author
Hiltensperger, Michael
author
Peter, Christian
author
Aly, Lilian
author
Knier, Benjamin
author
Palam, Lakshmi Reddy
author
Kapur, Reuben
author
Kaplan, Mark H
author
Waisman, Ari
author
Rad, Roland
author
Schotta, Gunnar
author
Huehn, Jochen
author
Kallies, Axel
author
Korn, Thomas
author
2019-02-12
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.
2211-1247
30759395
10.1016/j.celrep.2019.01.070
http://hdl.handle.net/10033/621696
Cell Reports
Blimp1
CNS
CNS2
DNA methyltransferases
Foxp3
Interleukin-6
epigenetic regulation
inflammation
regulatory T cells
Blimp1 Prevents Methylation of Foxp3 and Loss of Regulatory T Cell Identity at Sites of Inflammation.
oai:repository.helmholtz-hzi.de:10033/6217192019-08-30T11:35:12Zcom_10033_128109com_10033_620644col_10033_128110col_10033_620646
00925njm 22002777a 4500
dc
Elfiky, Ahmed
author
Bonifacius, Agnes
author
Pezoldt, Joern
author
Pasztoi, Maria
author
Chaoprasid, Paweena
author
Sadana, Pooja
author
El-Sherbeeny, Nagla
author
Hagras, Magda
author
Scrima, Andrea
author
Dersch, Petra
author
Huehn, Jochen
author
2018-12-23
Adaptive immunity is essentially required to control acute infection with enteropathogenic
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
Foxp3
Yersinia outer proteins
Yersinia pseudotuberculosis
cytotoxic necrotizing factor y
invasins
regulatory T cells
Yersinia Pseudotuberculosis Modulates Regulatory T Cell Stability via Injection of Yersinia Outer Proteins in a Type III Secretion System-Dependent Manner.
oai:repository.helmholtz-hzi.de:10033/6217312019-08-30T11:33:04Zcom_10033_128109com_10033_311624com_10033_6839col_10033_128110col_10033_311625
00925njm 22002777a 4500
dc
Łyszkiewicz, Marcin
author
Winter, Samantha J
author
Witzlau, Katrin
author
Föhse, Lisa
author
Brownlie, Rebecca
author
Puchałka, Jacek
author
Verheyden, Nikita A
author
Kunze-Schumacher, Heike
author
Imelmann, Esther
author
Blume, Jonas
author
Raha, Solaiman
author
Sekiya, Takashi
author
Yoshimura, Akihiko
author
Frueh, Jochen T
author
Ullrich, Evelyn
author
Huehn, Jochen
author
Weiss, Siegfried
author
Gutierrez, Maximiliano G
author
Prinz, Immo
author
Zamoyska, Rose
author
Ziętara, Natalia
author
Krueger, Andreas
author
2019-03-01
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.
1545-7885
30856173
10.1371/journal.pbio.2006716
http://hdl.handle.net/10033/621731
PLOS Biology
miR-181a/b-1 controls thymic selection of Treg cells and tunes their suppressive capacity.
oai:repository.helmholtz-hzi.de:10033/6217722019-08-30T11:24:25Zcom_10033_620591com_10033_128109col_10033_621771col_10033_620599
00925njm 22002777a 4500
dc
Waldt, Natalie
author
Seifert, Anke
author
Demiray, Yunus Emre
author
Devroe, Eric
author
Turk, Benjamin E
author
Reichardt, Peter
author
Mix, Charlie
author
Reinhold, Annegret
author
Freund, Christian
author
Müller, Andreas J
author
Schraven, Burkhart
author
Stork, Oliver
author
Kliche, Stefanie
author
2018-01-01
The integrin LFA-1 (CD11a/CD18) plays a critical role in the interaction of T cells with antigen presenting cells (APCs) to promote lymphocyte differentiation and proliferation. This integrin can be present either in a closed or in an open active conformation and its activation upon T-cell receptor (TCR) stimulation is a critical step to allow interaction with APCs. In this study we demonstrate that the serine/threonine kinase Ndr2 is critically involved in the initiation of TCR-mediated LFA-1 activation (open conformation) in T cells. Ndr2 itself becomes activated upon TCR stimulation and phosphorylates the intracellular integrin binding partner Filamin A (FLNa) at serine 2152. This phosphorylation promotes the dissociation of FLNa from LFA-1, allowing for a subsequent association of Talin and Kindlin-3 which both stabilize the open conformation of LFA-1. Our data suggest that Ndr2 activation is a crucial step to initiate TCR-mediated LFA-1 activation in T cells.
Front Immunol. 2018 Dec 4;9:2852. doi: 10.3389/fimmu.2018.02852. eCollection 2018.
1664-3224
30568657
10.3389/fimmu.2018.02852
http://hdl.handle.net/10033/621772
Frontiers in immunology
Filamin A
Kindlin-3
LFA-1
Ndr2
T cells
TCR
Talin
inside-out signaling
Filamin A Phosphorylation at Serine 2152 by the Serine/Threonine Kinase Ndr2 Controls TCR-Induced LFA-1 Activation in T Cells.
oai:repository.helmholtz-hzi.de:10033/6218062019-08-30T11:28:19Zcom_10033_620591com_10033_128109com_10033_620618col_10033_621771col_10033_620599col_10033_620621
00925njm 22002777a 4500
dc
Seiß, Elena A
author
Krone, Anna
author
Formaglio, Pauline
author
Goldmann, Oliver
author
Engelmann, Susanne
author
Schraven, Burkhart
author
Medina, Eva
author
Müller, Andreas J
author
2019-04-05
Upon the onset of inflammatory responses, bacterial pathogens are confronted with altered tissue microenvironments which can critically impact on their metabolic activity and growth. Changes in these parameters have however remained difficult to analyze over time, which would be critical to dissect the interplay between the host immune response and pathogen physiology. Here, we established an in vivo biosensor for measuring the growth rates of Staphylococcus aureus (S. aureus) on a single cell-level over days in an ongoing cutaneous infection. Using intravital 2-photon imaging and quantitative fluorescence microscopy, we show that upon neutrophil recruitment to the infection site and bacterial uptake, non-lethal dampening of S. aureus proliferation occurred. This inhibition was supported by NADPH oxidase activity. Therefore, reactive oxygen production contributes to pathogen containment within neutrophils not only by killing S. aureus, but also by restricting the growth rate of the bacterium.
Sci Rep. 2019 Apr 5;9(1):5703. doi: 10.1038/s41598-019-42129-6.
2045-2322
30952906
10.1038/s41598-019-42129-6
http://hdl.handle.net/10033/621806
Scientific Reports
Longitudinal proliferation mapping in vivo reveals NADPH oxidase-mediated dampening of Staphylococcus aureus growth rates within neutrophils.
oai:repository.helmholtz-hzi.de:10033/6218282019-08-30T11:29:44Zcom_10033_128109col_10033_621829
00925njm 22002777a 4500
dc
Luebke, Tobias
author
Schwarz, Lisa
author
Beer, Yan Yan
author
Schumann, Sabrina
author
Misterek, Maria
author
Sander, Frida Ewald
author
Plaza-Sirvent, Carlos
author
Schmitz, Ingo
author
2019-05-16
Clear cell renal cell carcinoma (ccRCC) is the most-prominent tumor type of kidney cancers. Resistance of renal cell carcinoma (RCC) against tumor therapy is often owing to apoptosis resistance, e.g., by overexpression of anti-apoptotic proteins. However, little is known about the role of the apoptosis inhibitor c-FLIP and its potential impact on death receptor-induced apoptosis in ccRCC cells. In this study, we demonstrate that c-FLIP is crucial for resistance against CD95L-induced apoptosis in four ccRCC cell lines. Strikingly, downregulation of c-FLIP expression by short hairpin RNA (shRNA)interference led to spontaneous caspase activation and apoptotic cell death. Of note, knockdown of all c-FLIP splice variants was required to induce apoptosis. Stimulation of ccRCC cells with CD95L induced NF-κB and MAP kinase survival pathways as revealed by phosphorylation of RelA/p65 and Erk1/2. Interestingly, CD95L surface expression was high in all cell lines analyzed, and CD95 but not TNF-R1 clustered at cell contact sites. Downstream of CD95, inhibition of the NF-κB pathway led to spontaneous cell death. Surprisingly, knockdown experiments revealed that c-FLIP inhibits NF-κB activation in the context of CD95 signaling. Thus, c-FLIP inhibits apoptosis and dampens NF-κB downstream of CD95 but allows NF-κB activation to a level sufficient for ccRCC cell survival. In summary, we demonstrate a complex CD95-FLIP-NF-κB-signaling circuit, in which CD95-CD95L interactions mediate a paracrine survival signal in ccRCC cells with c-FLIP and NF-κB both being required for inhibiting cell death and ensuring survival. Our findings might lead to novel therapeutic approaches of RCC by circumventing apoptosis resistance.
Cell Death Dis. 2019 May 16;10(6):384. doi: 10.1038/s41419-019-1609-y.
2041-4889
31097685
10.1038/s41419-019-1609-y
http://hdl.handle.net/10033/621828
Cell Death and Disease
c-FLIP and CD95 signaling are essential for survival of renal cell carcinoma.
oai:repository.helmholtz-hzi.de:10033/6218632019-07-13T02:26:12Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Pandiyan, Pushpa
author
Bhaskaran, Natarajan
author
Zou, Mangge
author
Schneider, Elizabeth
author
Jayaraman, Sangeetha
author
Huehn, Jochen
author
2019-01-01
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.
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
Th17
Treg
antibiotics
inflammation
microbiome
mucosa
mucosal immunity
resident microbes
Microbiome Dependent Regulation of T and Th17 Cells in Mucosa.
oai:repository.helmholtz-hzi.de:10033/6218742019-08-30T11:26:40Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Pandiyan, Pushpa
author
Bhaskaran, Natarajan
author
Zou, Mangge
author
Schneider, Elizabeth
author
Jayaraman, Sangeetha
author
Huehn, Jochen
author
2019-01-01
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.
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
Th17
Treg
antibiotics
inflammation
microbiome
mucosa
mucosal immunity
resident microbes
Microbiome Dependent Regulation of Tregs and Th17 Cells in Mucosa.
oai:repository.helmholtz-hzi.de:10033/6219112019-08-30T11:26:41Zcom_10033_128109col_10033_621829col_10033_128110
00925njm 22002777a 4500
dc
Schuster, Marc
author
Plaza-Sirvent, Carlos
author
Visekruna, Alexander
author
Huehn, Jochen
author
Schmitz, Ingo
author
2019-01-01
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.
1664-3224
31354726
10.3389/fimmu.2019.01583
http://hdl.handle.net/10033/621911
Frontiers in Immunology
NF-κB
cell differentiation
common γ-chain cytokines
regulatory T cell
thymus
transcription factor
Generation of Foxp3CD25 Regulatory T-Cell Precursors Requires c-Rel and IκB.
oai:repository.helmholtz-hzi.de:10033/6220092019-11-08T02:20:50Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Cossarizza, Andrea
author
Chang, Hyun-Dong
author
Radbruch, Andreas
author
Acs, Andreas
author
Adam, Dieter
author
Adam-Klages, Sabine
author
Agace, William W
author
Aghaeepour, Nima
author
Akdis, Mübeccel
author
Allez, Matthieu
author
Almeida, Larissa Nogueira
author
Alvisi, Giorgia
author
Anderson, Graham
author
Andrä, Immanuel
author
Annunziato, Francesco
author
Anselmo, Achille
author
Bacher, Petra
author
Baldari, Cosima T
author
Bari, Sudipto
author
Barnaba, Vincenzo
author
Barros-Martins, Joana
author
Battistini, Luca
author
Bauer, Wolfgang
author
Baumgart, Sabine
author
Baumgarth, Nicole
author
Baumjohann, Dirk
author
Baying, Bianka
author
Bebawy, Mary
author
Becher, Burkhard
author
Beisker, Wolfgang
author
Benes, Vladimir
author
Beyaert, Rudi
author
Blanco, Alfonso
author
Boardman, Dominic A
author
Bogdan, Christian
author
Borger, Jessica G
author
Borsellino, Giovanna
author
Boulais, Philip E
author
Bradford, Jolene A
author
Brenner, Dirk
author
Brinkman, Ryan R
author
Brooks, Anna E S
author
Busch, Dirk H
author
Büscher, Martin
author
Bushnell, Timothy P
author
Calzetti, Federica
author
Cameron, Garth
author
Cammarata, Ilenia
author
Cao, Xuetao
author
Cardell, Susanna L
author
Casola, Stefano
author
Cassatella, Marco A
author
Cavani, Andrea
author
Celada, Antonio
author
Chatenoud, Lucienne
author
Chattopadhyay, Pratip K
author
Chow, Sue
author
Christakou, Eleni
author
Čičin-Šain, Luka
author
Clerici, Mario
author
Colombo, Federico S
author
Cook, Laura
author
Cooke, Anne
author
Cooper, Andrea M
author
Corbett, Alexandra J
author
Cosma, Antonio
author
Cosmi, Lorenzo
author
Coulie, Pierre G
author
Cumano, Ana
author
Cvetkovic, Ljiljana
author
Dang, Van Duc
author
Dang-Heine, Chantip
author
Davey, Martin S
author
Davies, Derek
author
De Biasi, Sara
author
Del Zotto, Genny
author
Dela Cruz, Gelo Victoriano
author
Delacher, Michael
author
Della Bella, Silvia
author
Dellabona, Paolo
author
Deniz, Günnur
author
Dessing, Mark
author
Di Santo, James P
author
Diefenbach, Andreas
author
Dieli, Francesco
author
Dolf, Andreas
author
Dörner, Thomas
author
Dress, Regine J
author
Dudziak, Diana
author
Dustin, Michael
author
Dutertre, Charles-Antoine
author
Ebner, Friederike
author
Eckle, Sidonia B G
author
Edinger, Matthias
author
Eede, Pascale
author
Ehrhardt, Götz R A
author
Eich, Marcus
author
Engel, Pablo
author
Engelhardt, Britta
author
Erdei, Anna
author
Esser, Charlotte
author
Everts, Bart
author
Evrard, Maximilien
author
Falk, Christine S
author
Fehniger, Todd A
author
Felipo-Benavent, Mar
author
Ferry, Helen
author
Feuerer, Markus
author
Filby, Andrew
author
Filkor, Kata
author
Fillatreau, Simon
author
Follo, Marie
author
Förster, Irmgard
author
Foster, John
author
Foulds, Gemma A
author
Frehse, Britta
author
Frenette, Paul S
author
Frischbutter, Stefan
author
Fritzsche, Wolfgang
author
Galbraith, David W
author
Gangaev, Anastasia
author
Garbi, Natalio
author
Gaudilliere, Brice
author
Gazzinelli, Ricardo T
author
Geginat, Jens
author
Gerner, Wilhelm
author
Gherardin, Nicholas A
author
Ghoreschi, Kamran
author
Gibellini, Lara
author
Ginhoux, Florent
author
Goda, Keisuke
author
Godfrey, Dale I
author
Goettlinger, Christoph
author
González-Navajas, Jose M
author
Goodyear, Carl S
author
Gori, Andrea
author
Grogan, Jane L
author
Grummitt, Daryl
author
Grützkau, Andreas
author
Haftmann, Claudia
author
Hahn, Jonas
author
Hammad, Hamida
author
Hämmerling, Günter
author
Hansmann, Leo
author
Hansson, Goran
author
Harpur, Christopher M
author
Hartmann, Susanne
author
Hauser, Andrea
author
Hauser, Anja E
author
Haviland, David L
author
Hedley, David
author
Hernández, Daniela C
author
Herrera, Guadalupe
author
Herrmann, Martin
author
Hess, Christoph
author
Höfer, Thomas
author
Hoffmann, Petra
author
Hogquist, Kristin
author
Holland, Tristan
author
Höllt, Thomas
author
Holmdahl, Rikard
author
Hombrink, Pleun
author
Houston, Jessica P
author
Hoyer, Bimba F
author
Huang, Bo
author
Huang, Fang-Ping
author
Huber, Johanna E
author
Huehn, Jochen
author
Hundemer, Michael
author
Hunter, Christopher A
author
Hwang, William Y K
author
Iannone, Anna
author
Ingelfinger, Florian
author
Ivison, Sabine M
author
Jäck, Hans-Martin
author
Jani, Peter K
author
Jávega, Beatriz
author
Jonjic, Stipan
author
Kaiser, Toralf
author
Kalina, Tomas
author
Kamradt, Thomas
author
Kaufmann, Stefan H E
author
Keller, Baerbel
author
Ketelaars, Steven L C
author
Khalilnezhad, Ahad
author
Khan, Srijit
author
Kisielow, Jan
author
Klenerman, Paul
author
Knopf, Jasmin
author
Koay, Hui-Fern
author
Kobow, Katja
author
Kolls, Jay K
author
Kong, Wan Ting
author
Kopf, Manfred
author
Korn, Thomas
author
Kriegsmann, Katharina
author
Kristyanto, Hendy
author
Kroneis, Thomas
author
Krueger, Andreas
author
Kühne, Jenny
author
Kukat, Christian
author
Kunkel, Désirée
author
Kunze-Schumacher, Heike
author
Kurosaki, Tomohiro
author
Kurts, Christian
author
Kvistborg, Pia
author
Kwok, Immanuel
author
Landry, Jonathan
author
Lantz, Olivier
author
Lanuti, Paola
author
LaRosa, Francesca
author
Lehuen, Agnès
author
LeibundGut-Landmann, Salomé
author
Leipold, Michael D
author
Leung, Leslie Y T
author
Levings, Megan K
author
Lino, Andreia C
author
Liotta, Francesco
author
Litwin, Virginia
author
Liu, Yanling
author
Ljunggren, Hans-Gustaf
author
Lohoff, Michael
author
Lombardi, Giovanna
author
Lopez, Lilly
author
López-Botet, Miguel
author
Lovett-Racke, Amy E
author
Lubberts, Erik
author
Luche, Herve
author
Ludewig, Burkhard
author
Lugli, Enrico
author
Lunemann, Sebastian
author
Maecker, Holden T
author
Maggi, Laura
author
Maguire, Orla
author
Mair, Florian
author
Mair, Kerstin H
author
Mantovani, Alberto
author
Manz, Rudolf A
author
Marshall, Aaron J
author
Martínez-Romero, Alicia
author
Martrus, Glòria
author
Marventano, Ivana
author
Maslinski, Wlodzimierz
author
Matarese, Giuseppe
author
Mattioli, Anna Vittoria
author
Maueröder, Christian
author
Mazzoni, Alessio
author
McCluskey, James
author
McGrath, Mairi
author
McGuire, Helen M
author
McInnes, Iain B
author
Mei, Henrik E
author
Melchers, Fritz
author
Melzer, Susanne
author
Mielenz, Dirk
author
Miller, Stephen D
author
Mills, Kingston H G
author
Minderman, Hans
author
Mjösberg, Jenny
author
Moore, Jonni
author
Moran, Barry
author
Moretta, Lorenzo
author
Mosmann, Tim R
author
Müller, Susann
author
Multhoff, Gabriele
author
Muñoz, Luis Enrique
author
Münz, Christian
author
Nakayama, Toshinori
author
Nasi, Milena
author
Neumann, Katrin
author
Ng, Lai Guan
author
Niedobitek, Antonia
author
Nourshargh, Sussan
author
Núñez, Gabriel
author
O'Connor, José-Enrique
author
Ochel, Aaron
author
Oja, Anna
author
Ordonez, Diana
author
Orfao, Alberto
author
Orlowski-Oliver, Eva
author
Ouyang, Wenjun
author
Oxenius, Annette
author
Palankar, Raghavendra
author
Panse, Isabel
author
Pattanapanyasat, Kovit
author
Paulsen, Malte
author
Pavlinic, Dinko
author
Penter, Livius
author
Peterson, Pärt
author
Peth, Christian
author
Petriz, Jordi
author
Piancone, Federica
author
Pickl, Winfried F
author
Piconese, Silvia
author
Pinti, Marcello
author
Pockley, A Graham
author
Podolska, Malgorzata Justyna
author
Poon, Zhiyong
author
Pracht, Katharina
author
Prinz, Immo
author
Pucillo, Carlo E M
author
Quataert, Sally A
author
Quatrini, Linda
author
Quinn, Kylie M
author
Radbruch, Helena
author
Radstake, Tim R D J
author
Rahmig, Susann
author
Rahn, Hans-Peter
author
Rajwa, Bartek
author
Ravichandran, Gevitha
author
Raz, Yotam
author
Rebhahn, Jonathan A
author
Recktenwald, Diether
author
Reimer, Dorothea
author
Reis E Sousa, Caetano
author
Remmerswaal, Ester B M
author
Richter, Lisa
author
Rico, Laura G
author
Riddell, Andy
author
Rieger, Aja M
author
Robinson, J Paul
author
Romagnani, Chiara
author
Rubartelli, Anna
author
Ruland, Jürgen
author
Saalmüller, Armin
author
Saeys, Yvan
author
Saito, Takashi
author
Sakaguchi, Shimon
author
Sala-de-Oyanguren, Francisco
author
Samstag, Yvonne
author
Sanderson, Sharon
author
Sandrock, Inga
author
Santoni, Angela
author
Sanz, Ramon Bellmàs
author
Saresella, Marina
author
Sautes-Fridman, Catherine
author
Sawitzki, Birgit
author
Schadt, Linda
author
Scheffold, Alexander
author
Scherer, Hans U
author
Schiemann, Matthias
author
Schildberg, Frank A
author
Schimisky, Esther
author
Schlitzer, Andreas
author
Schlosser, Josephine
author
Schmid, Stephan
author
Schmitt, Steffen
author
Schober, Kilian
author
Schraivogel, Daniel
author
Schuh, Wolfgang
author
Schüler, Thomas
author
Schulte, Reiner
author
Schulz, Axel Ronald
author
Schulz, Sebastian R
author
Scottá, Cristiano
author
Scott-Algara, Daniel
author
Sester, David P
author
Shankey, T Vincent
author
Silva-Santos, Bruno
author
Simon, Anna Katharina
author
Sitnik, Katarzyna M
author
Sozzani, Silvano
author
Speiser, Daniel E
author
Spidlen, Josef
author
Stahlberg, Anders
author
Stall, Alan M
author
Stanley, Natalie
author
Stark, Regina
author
Stehle, Christina
author
Steinmetz, Tobit
author
Stockinger, Hannes
author
Takahama, Yousuke
author
Takeda, Kiyoshi
author
Tan, Leonard
author
Tárnok, Attila
author
Tiegs, Gisa
author
Toldi, Gergely
author
Tornack, Julia
author
Traggiai, Elisabetta
author
Trebak, Mohamed
author
Tree, Timothy I M
author
Trotter, Joe
author
Trowsdale, John
author
Tsoumakidou, Maria
author
Ulrich, Henning
author
Urbanczyk, Sophia
author
van de Veen, Willem
author
van den Broek, Maries
author
van der Pol, Edwin
author
Van Gassen, Sofie
author
Van Isterdael, Gert
author
van Lier, René A W
author
Veldhoen, Marc
author
Vento-Asturias, Salvador
author
Vieira, Paulo
author
Voehringer, David
author
Volk, Hans-Dieter
author
von Borstel, Anouk
author
von Volkmann, Konrad
author
Waisman, Ari
author
Walker, Rachael V
author
Wallace, Paul K
author
Wang, Sa A
author
Wang, Xin M
author
Ward, Michael D
author
Ward-Hartstonge, Kirsten A
author
Warnatz, Klaus
author
Warnes, Gary
author
Warth, Sarah
author
Waskow, Claudia
author
Watson, James V
author
Watzl, Carsten
author
Wegener, Leonie
author
Weisenburger, Thomas
author
Wiedemann, Annika
author
Wienands, Jürgen
author
Wilharm, Anneke
author
Wilkinson, Robert John
author
Willimsky, Gerald
author
Wing, James B
author
Winkelmann, Rieke
author
Winkler, Thomas H
author
Wirz, Oliver F
author
Wong, Alicia
author
Wurst, Peter
author
Yang, Jennie H M
author
Yang, Juhao
author
Yazdanbakhsh, Maria
author
Yu, Liping
author
Yue, Alice
author
Zhang, Hanlin
author
Zhao, Yi
author
Ziegler, Susanne Maria
author
Zielinski, Christina
author
Zimmermann, Jakob
author
Zychlinsky, Arturo
author
2019-10-01
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.
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
Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition).
oai:repository.helmholtz-hzi.de:10033/6220312019-11-27T02:00:58Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Herppich, Susanne
author
Toker, Aras
author
Pietzsch, Beate
author
Kitagawa, Yohko
author
Ohkura, Naganari
author
Miyao, Takahisa
author
Floess, Stefan
author
Hori, Shohei
author
Sakaguchi, Shimon
author
Huehn, Jochen
author
2019-01-01
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.
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
Foxp3
IL-2
TSDR
Treg cell
Treg cell precursors
demethylation
epigenetic signature
thymus
Dynamic Imprinting of the Treg Cell-Specific Epigenetic Signature in Developing Thymic Regulatory T Cells.
oai:repository.helmholtz-hzi.de:10033/6220482019-12-12T02:00:20Zcom_10033_128109col_10033_621829
00925njm 22002777a 4500
dc
Presa, Maximiliano
author
Racine, Jeremy J
author
Dwyer, Jennifer R
author
Lamont, Deanna J
author
Ratiu, Jeremy J
author
Sarsani, Vishal Kumar
author
Chen, Yi-Guang
author
Geurts, Aron
author
Schmitz, Ingo
author
Stearns, Timothy
author
Allocco, Jennifer
author
Chapman, Harold D
author
Serreze, David V
author
2018-10-01
In both NOD mice and humans, the development of type 1 diabetes (T1D) is dependent in part on autoreactive CD8+ T cells recognizing pancreatic β cell peptides presented by often quite common MHC class I variants. Studies in NOD mice previously revealed that the common H2-Kd and/or H2-Db class I molecules expressed by this strain aberrantly lose the ability to mediate the thymic deletion of pathogenic CD8+ T cell responses through interactions with T1D susceptibility genes outside the MHC. A gene(s) mapping to proximal chromosome 7 was previously shown to be an important contributor to the failure of the common class I molecules expressed by NOD mice to mediate the normal thymic negative selection of diabetogenic CD8+ T cells. Using an inducible model of thymic negative selection and mRNA transcript analyses, we initially identified an elevated Nfkbid expression variant as a likely NOD-proximal chromosome 7 region gene contributing to impaired thymic deletion of diabetogenic CD8+ T cells. CRISPR/Cas9-mediated genetic attenuation of Nfkbid expression in NOD mice resulted in improved negative selection of autoreactive diabetogenic AI4 and NY8.3 CD8+ T cells. These results indicated that allelic variants of Nfkbid contribute to the efficiency of intrathymic deletion of diabetogenic CD8+ T cells. However, although enhancing thymic deletion of pathogenic CD8+ T cells, ablating Nfkbid expression surprisingly accelerated T1D onset that was associated with numeric decreases in both regulatory T and B lymphocytes in NOD mice.
J Immunol. 2018 Oct 1;201(7):1907-1917. doi: 10.4049/jimmunol.1800465. Epub 2018 Aug 20.
1550-6606
30127089
10.4049/jimmunol.1800465
http://hdl.handle.net/10033/622048
Journal of Immunology
PMC6153649
A Hypermorphic Allele Contributes to Impaired Thymic Deletion of Autoreactive Diabetogenic CD8 T Cells in NOD Mice.
oai:repository.helmholtz-hzi.de:10033/6220742020-01-11T02:14:02Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Andersen, Liisa
author
Gülich, Alexandra Franziska
author
Alteneder, Marlis
author
Preglej, Teresa
author
Orola, Maria Jonah
author
Dhele, Narendra
author
Stolz, Valentina
author
Schebesta, Alexandra
author
Hamminger, Patricia
author
Hladik, Anastasiya
author
Floess, Stefan
author
Krausgruber, Thomas
author
Faux, Thomas
author
Andrabi, Syed Bilal Ahmad
author
Huehn, Jochen
author
Knapp, Sylvia
author
Sparwasser, Tim
author
Bock, Christoph
author
Laiho, Asta
author
Elo, Laura L
author
Rasool, Omid
author
Lahesmaa, Riitta
author
Sakaguchi, Shinya
author
Ellmeier, Wilfried
author
2019-12-24
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.
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
DSS-induced colitis
FOXP3
MAZR
PATZ1
T(reg)
regulatory T cells
The Transcription Factor MAZR/PATZ1 Regulates the Development of FOXP3 Regulatory T Cells.
oai:repository.helmholtz-hzi.de:10033/6220782020-01-15T02:19:12Zcom_10033_128109col_10033_621829
00925njm 22002777a 4500
dc
Luu, Maik
author
Romero, Rossana
author
Bazant, Jasmin
author
Abass, Elfadil
author
Hartmann, Sabrina
author
Leister, Hanna
author
Fischer, Florence
author
Mahdavi, Rouzbeh
author
Plaza-Sirvent, Carlos
author
Schmitz, Ingo
author
Steinhoff, Ulrich
author
Visekruna, Alexander
author
2019-11-14
Mice lacking CD4+ T cells or B cells are highly susceptible to Citrobacter rodentium infection. In this study, we show that the activity of the transcription factor c-Rel in lymphocytes is crucial for clearance of C. rodentium. Mice deficient for c-Rel fail to generate protective antibodies and to eradicate the pathogen.
Eur J Immunol. 2019 Nov 14. doi: 10.1002/eji.201948314.
1521-4141
31724737
10.1002/eji.201948314
http://hdl.handle.net/10033/622078
European Journal of Immunology
B cells
CD4+ T cells
Citrobacter rodentium
NF-κB
c-Rel
The NF-κB transcription factor c-Rel controls host defense against Citrobacter rodentium.
oai:repository.helmholtz-hzi.de:10033/6221012020-01-22T02:27:15Zcom_10033_128109com_10033_620636col_10033_128110col_10033_620638
00925njm 22002777a 4500
dc
Maluski, Marcel
author
Ghosh, Arnab
author
Herbst, Jessica
author
Scholl, Vanessa
author
Baumann, Rolf
author
Huehn, Jochen
author
Geffers, Robert
author
Meyer, Johann
author
Maul, Holger
author
Eiz-Vesper, Britta
author
Krueger, Andreas
author
Schambach, Axel
author
van den Brink, Marcel Rm
author
Sauer, Martin G
author
2019-12-02
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.
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
Immunology
Immunotherapy
Leukemias
T cell development
Transplantation
Chimeric antigen receptor-induced BCL11B suppression propagates NK-like cell development.
oai:repository.helmholtz-hzi.de:10033/6221162020-02-05T02:17:07Zcom_10033_128109col_10033_621771
00925njm 22002777a 4500
dc
Bui, Viet D.
author
Mwangi, James W.
author
Meinshausen, Ann-Kathrin
author
Mueller, Andreas J.
author
Bertrand, Jessica
author
Schubert, Andreas
author
2020-02
Previous studies have revealed the potential of powder mixed electrical discharge machining (PMEDM) with regards to concurrently machining part geometry and coating an antibacterial layer on medical devices. This study is aimed at further demonstrating this potential. In order to do so, the PMEDM process was varied by adding different concentrations of silver nano-particles into the dielectric fluid and used to machine Ti-6Al-4V. Afterwards, the resulting machined and coated surfaces were characterized with regards to surface integrity, the coating layer's thickness, microhardness and chemical elements as well as antibacterial property. Material removal rate, tool wear and pulse signals were also analysed in order to give an insight on process feasibility. From both qualitative and quantitative results, it could be established that the surfaces machined and coated by PMEDM method have demonstrated a significant reduction of not only the amount of S. aureus bacteria, but also the number of bacterial clusters on the coating layer's surface. Moreover, the coating layer's silver content, which depends on the powder concentration suspended in the dielectric fluid, plays a vital role in the antibacterial property. As compared to surfaces without silver, surfaces containing approximately 3.78% silver content showed a significant decrease in both bacterial numbers and clusters, whereas a further increase in silver content did not result in a considerable bacterial number and cluster reduction. Regarding the machining performance, as compared to EDM without powder, machining time is remarkably decreased by using the PMEDM method.
0257-8972
10.1016/j.surfcoat.2019.125254
http://hdl.handle.net/10033/622116
Surface and Coatings Technology
Materials Chemistry
General Chemistry
Surfaces, Coatings and Films
Surfaces and Interfaces
Condensed Matter Physics
Antibacterial coating of Ti-6Al-4V surfaces using silver nano-powder mixed electrical discharge machining
oai:repository.helmholtz-hzi.de:10033/6221482020-02-20T02:04:23Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Nikolouli, Eirini
author
Elfaki, Yassin
author
Herppich, Susanne
author
Schelmbauer, Carsten
author
Delacher, Michael
author
Falk, Christine
author
Mufazalov, Ilgiz A
author
Waisman, Ari
author
Feuerer, Markus
author
Huehn, Jochen
author
2020-01-27
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.
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
IL-1 system
Inflammation
Thymus
Treg development
Recirculating IL-1R2 Tregs fine-tune intrathymic Treg development under inflammatory conditions.
oai:repository.helmholtz-hzi.de:10033/6221862020-03-11T02:09:21Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Andersen, Liisa
author
Gülich, Alexandra Franziska
author
Alteneder, Marlis
author
Preglej, Teresa
author
Orola, Maria Jonah
author
Dhele, Narendra
author
Stolz, Valentina
author
Schebesta, Alexandra
author
Hamminger, Patricia
author
Hladik, Anastasiya
author
Floess, Stefan
author
Krausgruber, Thomas
author
Faux, Thomas
author
Andrabi, Syed Bilal Ahmad
author
Huehn, Jochen
author
Knapp, Sylvia
author
Sparwasser, Tim
author
Bock, Christoph
author
Laiho, Asta
author
Elo, Laura L
author
Rasool, Omid
author
Lahesmaa, Riitta
author
Sakaguchi, Shinya
author
Ellmeier, Wilfried
author
2019-12-24
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.
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
DSS-induced colitis
FOXP3
MAZR
PATZ1
T(reg)
regulatory T cells
The Transcription Factor MAZR/PATZ1 Regulates the Development of FOXP3 Regulatory T Cells.
oai:repository.helmholtz-hzi.de:10033/6221942020-03-11T02:08:36Zcom_10033_621723com_10033_128109col_10033_621724col_10033_621829
00925njm 22002777a 4500
dc
Bank, Ute
author
Deiser, Katrin
author
Plaza-Sirvent, Carlos
author
Osbelt, Lisa
author
Witte, Amelie
author
Knop, Laura
author
Labrenz, Rebecca
author
Jänsch, Robert
author
Richter, Felix
author
Biswas, Aindrila
author
Zenclussen, Ana C
author
Vivier, Eric
author
Romagnani, Chiara
author
Kühl, Anja A
author
Dunay, Ildiko R
author
Strowig, Till
author
Schmitz, Ingo
author
Schüler, Thomas
author
2020-02-26
NKp46+ innate lymphoid cells (ILC) modulate tissue homeostasis and anti-microbial immune responses. ILC development and function are regulated by cytokines such as Interleukin (IL)-7 and IL-15. However, the ILC-intrinsic pathways translating cytokine signals into developmental programs are largely unknown. Here we show that the anti-apoptotic molecule cellular FLICE-like inhibitory protein (c-FLIP) is crucial for the generation of IL-7/IL-15-dependent NKp46+ ILC1, including conventional natural killer (cNK) cells, and ILC3. Cytokine-induced phosphorylation of signal transducer and activator of transcription 5 (STAT5) precedes up-regulation of c-FLIP, which protects developing NKp46+ ILC from TNF-induced apoptosis. NKp46+ ILC-specific inactivation of c-FLIP leads to the loss of all IL-7/IL-15-dependent NKp46+ ILC, thereby inducing early-onset chronic colitis and subsequently microbial dysbiosis; meanwhile, the depletion of cNK, but not NKp46+ ILC1/3, aggravates experimental colitis. In summary, our data demonstrate a non-redundant function of c-FLIP for the generation of NKp46+ ILC, which protect T/B lymphocyte-sufficient mice from intestinal inflammation.
Nat Commun. 2020 Feb 26;11(1):1056. doi: 10.1038/s41467-020-14782-3.
2041-1723
32103006
10.1038/s41467-020-14782-3
http://hdl.handle.net/10033/622194
Nature communications
c-FLIP is crucial for IL-7/IL-15-dependent NKp46 ILC development and protection from intestinal inflammation in mice.
oai:repository.helmholtz-hzi.de:10033/6222562020-05-13T01:29:17Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Kouakanou, Léonce
author
Peters, Christian
author
Sun, Qiwei
author
Floess, Stefan
author
Bhat, Jaydeep
author
Huehn, Jochen
author
Kabelitz, Dieter
author
2020-04-16
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
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
Vitamin C supports conversion of human γδ T cells into FOXP3-expressing regulatory cells by epigenetic regulation.
oai:repository.helmholtz-hzi.de:10033/6223052020-06-23T03:31:11Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Kyburz, Andreas
author
Fallegger, Angela
author
Zhang, Xiaozhou
author
Altobelli, Aleksandra
author
Artola-Boran, Mariela
author
Borbet, Timothy
author
Urban, Sabine
author
Paul, Petra
author
Münz, Christian
author
Floess, Stefan
author
Huehn, Jochen
author
Cover, Timothy L
author
Blaser, Martin J
author
Taube, Christian
author
Müller, Anne
author
2018-09-19
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.
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
Allergic airway inflammation
epigenetic regulation of allergy and asthma
immune regulation
immune tolerance
metagenomics
microbial interventions during pregnancy
Transmaternal Helicobacter pylori exposure reduces allergic airway inflammation in offspring through regulatory T cells.
oai:repository.helmholtz-hzi.de:10033/6223142020-06-26T02:39:29Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Matthias, Julia
author
Heink, Sylvia
author
Picard, Felix Sr
author
Zeiträg, Julia
author
Kolz, Anna
author
Chao, Ying-Yin
author
Soll, Dominik
author
de Almeida, Gustavo P
author
Glasmacher, Elke
author
Jacobsen, Ilse D
author
Riedel, Thomas
author
Peters, Anneli
author
Floess, Stefan
author
Huehn, Jochen
author
Baumjohann, Dirk
author
Huber, Magdalena
author
Korn, Thomas
author
Zielinski, Christina E
author
2020-06-02
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.
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
Adaptive immunity
Immunology
Inflammation
T cells
Salt generates anti-inflammatory Th17 cells but amplifies their pathogenicity in pro-inflammatory cytokine microenvironments.
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
00925njm 22002777a 4500
dc
Bonifacius, Agnes
author
Goldmann, Oliver
author
Floess, Stefan
author
Holtfreter, Silva
author
Robert, Philippe A
author
Nordengrün, Maria
author
Kruse, Friederike
author
Lochner, Matthias
author
Falk, Christine S
author
Schmitz, Ingo
author
Bröker, Barbara M
author
Medina, Eva
author
Huehn, Jochen
author
2020-08-07
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.
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
CD4+ T cells
Staphylococcus aureus
alpha-toxin
innate lymphoid cells
γδ T cells
Staphylococcus aureus Alpha-Toxin Limits Type 1 While Fostering Type 3 Immune Responses.
oai:repository.helmholtz-hzi.de:10033/6225402020-11-04T04:36:51Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Zou, Mangge
author
Yang, Juhao
author
Wiechers, Carolin
author
Huehn, Jochen
author
2020-06-19
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.
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
immune system
listeria monocytogenes
long-term consequences
neonatal infection
organ-specific
Acute neonatal Listeria monocytogenes infection causes long-term, organ-specific changes in immune cell subset composition.
oai:repository.helmholtz-hzi.de:10033/6225902020-11-18T01:33:34Zcom_10033_128109col_10033_621829
00925njm 22002777a 4500
dc
Shah, Aneri
author
Plaza-Sirvent, Carlos
author
Weinert, Sönke
author
Buchbinder, Jörn H
author
Lavrik, Inna N
author
Mertens, Peter R
author
Schmitz, Ingo
author
Lindquist, Jonathan A
author
2020-08-05
Cell fate decisions regulating survival and death are essential for maintaining tissue homeostasis; dysregulation thereof can lead to tumor development. In some cases, survival and death are triggered by the same receptor, e.g., tumor necrosis factor (TNF)-receptor 1 (TNFR1). We identified a prominent role for the cold shock Y-box binding protein-1 (YB-1) in the TNF-induced activation and nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65. In the absence of YB-1, the expression of TNF receptor-associated factor 2 (TRAF2), a central component of the TNF receptor signaling complex required for NF-κB activation, is significantly reduced. Therefore, we hypothesized that the loss of YB-1 results in a destabilization of TRAF2. Consistent with this hypothesis, we observed that YB-1-deficient cells were more prone to TNF-induced apoptotic cell death. We observed enhanced effector caspase-3 activation and could successfully rescue the cells using the pan-caspase inhibitor zVAD-fmk, but not necrostatin-1. Taken together, our results indicate that YB-1 plays a central role in promoting cell survival through NF-κB activation and identifies a novel mechanism by which enhanced YB-1 expression may contribute to tumor development.
Cancers (Basel). 2020 Aug 5;12(8):2188. doi: 10.3390/cancers12082188.
2072-6694
32764479
10.3390/cancers12082188
http://hdl.handle.net/10033/622590
Cancers
TNF
apoptosis
cold shock proteins
YB-1 Mediates TNF-Induced Pro-Survival Signaling by Regulating NF-κB Activation.
oai:repository.helmholtz-hzi.de:10033/6227062021-01-28T01:39:39Zcom_10033_128109col_10033_620747
00925njm 22002777a 4500
dc
Fabits, Markus
author
Gonçalves Magalhães, Vladimir
author
Chan, Baca
author
Girault, Virginie
author
Elbasani, Endrit
author
Rossetti, Elisa
author
Saeland, Eirikur
author
Messerle, Martin
author
Pichlmair, Andreas
author
Lisnić, Vanda Juranić
author
Brinkmann, Melanie M
author
2020-05-26
The rapid activation of pattern recognition receptor (PRR)-mediated type I interferon (IFN) signaling is crucial for the host response to infection. In turn, human cytomegalovirus (HCMV) must evade this potent response to establish life-long infection. Here, we reveal that the HCMV tegument protein UL35 antagonizes the activation of type I IFN transcription downstream of the DNA and RNA sensors cGAS and RIG-I, respectively. We show that ectopic expression of UL35 diminishes the type I IFN response, while infection with a recombinant HCMV lacking UL35 induces an elevated type I IFN response compared to wildtype HCMV. With a series of luciferase reporter assays and the analysis of signaling kinetics upon HCMV infection, we observed that UL35 downmodulates PRR signaling at the level of the key signaling factor TANK-binding kinase 1 (TBK1). Finally, we demonstrate that UL35 and TBK1 co-immunoprecipitate when co-expressed in HEK293T cells. In addition, we show that a previously reported cellular binding partner of UL35, O-GlcNAc transferase (OGT), post-translationally GlcNAcylates UL35, but that this modification is not required for the antagonizing effect of UL35 on PRR signaling. In summary, we have identified UL35 as the first HCMV protein to antagonize the type I IFN response at the level of TBK1, thereby enriching our understanding of how this important herpesvirus escapes host immune responses.
Microorganisms. 2020 May 26;8(6):790. doi: 10.3390/microorganisms8060790.
2076-2607
32466380
10.3390/microorganisms8060790
http://hdl.handle.net/10033/622706
Microorganisms
herpesvirus, cytomegalovirus, pattern recognition receptor, cGAS, STING, RIG-I, TBK1, UL35, type I interferon, OGT
herpesvirus
cytomegalovirus
pattern recognition receptor
cGAS
STING
RIG-I
TBK1
The Cytomegalovirus Tegument Protein UL35 Antagonizes Pattern Recognition Receptor-Mediated Type I IFN Transcription.
oai:repository.helmholtz-hzi.de:10033/6227402021-02-16T03:17:28Zcom_10033_128109col_10033_621829
00925njm 22002777a 4500
dc
Riebisch, Anna K
author
Mühlen, Sabrina
author
Beer, Yan Yan
author
Schmitz, Ingo
author
2021-01-22
Autophagy is a highly conserved and fundamental cellular process to maintain cellular homeostasis through recycling of defective organelles or proteins. In a response to intracellular pathogens, autophagy further acts as an innate immune response mechanism to eliminate pathogens. This review will discuss recent findings on autophagy as a reaction to intracellular pathogens, such as Salmonella typhimurium, Listeria monocytogenes, Mycobacterium tuberculosis, Staphylococcus aureus, and pathogenic Escherichia coli. Interestingly, while some of these bacteria have developed methods to use autophagy for their own benefit within the cell, others have developed fascinating mechanisms to evade recognition, to subvert the autophagic pathway, or to escape from autophagy.
Pathogens. 2021 Jan 22;10(2):110. doi: 10.3390/pathogens10020110.
2076-0817
33499114
10.3390/pathogens10020110
http://hdl.handle.net/10033/622740
Pathogens (Basel, Switzerland)
autophagy
innate immune response
pathogens
pattern recognition receptors
xenophagy
Autophagy-A Story of Bacteria Interfering with the Host Cell Degradation Machinery.
oai:repository.helmholtz-hzi.de:10033/6227482021-02-18T04:37:51Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Permanyer, Marc
author
Bošnjak, Berislav
author
Glage, Silke
author
Friedrichsen, Michaela
author
Floess, Stefan
author
Huehn, Jochen
author
Patzer, Gwendolyn E
author
Odak, Ivan
author
Eckert, Nadine
author
Zargari, Razieh
author
Ospina-Quintero, Laura
author
Georgiev, Hristo
author
Förster, Reinhold
author
2021-01-06
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.
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
IL-2R signaling
Regulatory T cells
Treg heterogeneity
scRNA sequencing
Efficient IL-2R signaling differentially affects the stability, function, and composition of the regulatory T-cell pool.
oai:repository.helmholtz-hzi.de:10033/6228122021-04-01T01:31:51Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Zou, Mangge
author
Wiechers, Carolin
author
Huehn, Jochen
author
2021-02-25
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.
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
Immune regulation
Infection and inflammation
Lymph node
Mucosal micro-environment
Stromal cells
Lymph node stromal cell subsets-Emerging specialists for tailored tissue-specific immune responses.
oai:repository.helmholtz-hzi.de:10033/6228232021-04-08T01:40:59Zcom_10033_128109com_10033_620659com_10033_620591col_10033_128110col_10033_620724col_10033_620660
00925njm 22002777a 4500
dc
Elfaki, Yassin
author
Robert, Philippe A
author
Binz, Christoph
author
Falk, Christine S
author
Bruder, Dunja
author
Prinz, Immo
author
Floess, Stefan
author
Meyer-Hermann, Michael
author
Huehn, Jochen
author
2021-02-26
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.
Eur J Immunol. 2021 Feb 26. doi: 10.1002/eji.202048981. Epub ahead of print.
33638148
10.1002/eji.202048981
http://hdl.handle.net/10033/622823
1521-4141
European journal of immunology
Foxp3+ Treg cells ⋅ Influenza A virus ⋅ Mathematical modeling ⋅ Ordinary differential equations ⋅ Thymus atrophy
Influenza A virus-induced thymus atrophy differentially affects dynamics of conventional and regulatory T-cell development in mice.
oai:repository.helmholtz-hzi.de:10033/6228512021-04-30T01:45:10Zcom_10033_128109com_10033_621723col_10033_621724col_10033_128110
00925njm 22002777a 4500
dc
Delacher, Michael
author
Simon, Malte
author
Sanderink, Lieke
author
Hotz-Wagenblatt, Agnes
author
Wuttke, Marina
author
Schambeck, Kathrin
author
Schmidleithner, Lisa
author
Bittner, Sebastian
author
Pant, Asmita
author
Ritter, Uwe
author
Hehlgans, Thomas
author
Riegel, Dania
author
Schneider, Verena
author
Groeber-Becker, Florian Kai
author
Eigenberger, Andreas
author
Gebhard, Claudia
author
Strieder, Nicholas
author
Fischer, Alexander
author
Rehli, Michael
author
Hoffmann, Petra
author
Edinger, Matthias
author
Strowig, Till
author
Huehn, Jochen
author
Schmidl, Christian
author
Werner, Jens M
author
Prantl, Lukas
author
Brors, Benedikt
author
Imbusch, Charles D
author
Feuerer, Markus
author
2021-03-30
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.
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
Single-cell chromatin accessibility landscape identifies tissue repair program in human regulatory T cells.
oai:repository.helmholtz-hzi.de:10033/6228592021-05-07T01:42:01Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Maus, Irena
author
Klocke, Michael
author
Derenkó, Jaqueline
author
Stolze, Yvonne
author
Beckstette, Michael
author
Jost, Carsten
author
Wibberg, Daniel
author
Blom, Jochen
author
Henke, Christian
author
Willenbücher, Katharina
author
Rumming, Madis
author
Rademacher, Antje
author
Pühler, Alfred
author
Sczyrba, Alexander
author
Schlüter, Andreas
author
2020-03-02
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.
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
Anaerobic digestion
Bioconversion
Biogas
Integrated -omics
Metabolic activity
Metagenome assembled genomes
Methane
Microbial community structure
Polyomics
Impact of process temperature and organic loading rate on cellulolytic / hydrolytic biofilm microbiomes during biomethanation of ryegrass silage revealed by genome-centered metagenomics and metatranscriptomics.
oai:repository.helmholtz-hzi.de:10033/6228902021-06-01T01:45:47Zcom_10033_128109com_10033_621723col_10033_621724col_10033_128110
00925njm 22002777a 4500
dc
Wiechers, Carolin
author
Zou, Mangge
author
Galvez, Eric
author
Beckstette, Michael
author
Ebel, Maria
author
Strowig, Till
author
Huehn, Jochen
author
Pezoldt, Joern
author
2021-03-24
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.
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
Microbiota
Peripheral regulatory T cells
Tolerance
The microbiota is dispensable for the early stages of peripheral regulatory T cell induction within mesenteric lymph nodes.
oai:repository.helmholtz-hzi.de:10033/6229102021-06-25T01:42:23Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Floess, Stefan
author
Huehn, Jochen
author
2021-04-30
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.
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.)
Epigenetic regulation
Methylome
Sequencing library
Generation of Sequencing Libraries for Building Immune Cell Methylomes.
oai:repository.helmholtz-hzi.de:10033/6229532021-07-23T01:43:30Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Ciurkiewicz, Malgorzata
author
Floess, Stefan
author
Beckstette, Michael
author
Kummerfeld, Maren
author
Baumgärtner, Wolfgang
author
Huehn, Jochen
author
Beineke, Andreas
author
2021-07-06
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.
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)
Theiler's murine encephalomyelitis virus
antigen presentation
antiviral response
demyelination
innate immune response
mouse model
neurotropic virus
transcriptome analysis
viral encephalitis
Transcriptome analysis following neurotropic virus infection reveals faulty innate immunity and delayed antigen presentation in mice susceptible to virus-induced demyelination.
oai:repository.helmholtz-hzi.de:10033/6230112021-09-02T02:41:49Zcom_10033_128109com_10033_622921col_10033_128110col_10033_622926
00925njm 22002777a 4500
dc
Elfaki, Yassin
author
Yang, Juhao
author
Boehme, Julia
author
Schultz, Kristin
author
Bruder, Dunja
author
Falk, Christine S
author
Huehn, Jochen
author
Floess, Stefan
author
2021-07-14
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.
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
Foxp3
Tbx21
Tregs
inflammation
influenza A virus
lung
methylation
Tbx21 and foxp3 are Epigenetically Stabilized in T-Bet Tregs That Transiently Accumulate in Influenza A Virus-Infected Lungs.
oai:repository.helmholtz-hzi.de:10033/6230172021-09-09T01:53:12Zcom_10033_128109com_10033_620659col_10033_128110col_10033_620660
00925njm 22002777a 4500
dc
Arulraj, Theinmozhi
author
Binder, Sebastian C
author
Robert, Philippe A
author
Meyer-Hermann, Michael
author
2021-07-07
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.
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
B cell lymphoma
antibody responses
chronic germinal centres
ectopic germinal centres
germinal centre shutdown
vaccination
Germinal Centre Shutdown.
oai:repository.helmholtz-hzi.de:10033/6230282021-09-15T01:54:16Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Shaikh, Haroon
author
Vargas, Juan Gamboa
author
Mokhtari, Zeinab
author
Jarick, Katja J
author
Ulbrich, Maria
author
Mosca, Josefina Peña
author
Viera, Estibaliz Arellano
author
Graf, Caroline
author
Le, Duc-Dung
author
Heinze, Katrin G
author
Büttner-Herold, Maike
author
Rosenwald, Andreas
author
Pezoldt, Joern
author
Huehn, Jochen
author
Beilhack, Andreas
author
2021-07-26
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.
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
acute graft-versus host disease
alloreactive T cells
lymph node stromal cells
lymph node transplantation
mesenteric lymph node
mouse models
Mesenteric Lymph Node Transplantation in Mice to Study Immune Responses of the Gastrointestinal Tract.
oai:repository.helmholtz-hzi.de:10033/6230822021-10-29T01:58:33Zcom_10033_620626com_10033_621723com_10033_128109col_10033_621724col_10033_621829col_10033_620629
00925njm 22002777a 4500
dc
Plaza-Sirvent, Carlos
author
Zhao, Bei
author
Bronietzki, Alisha W
author
Pils, Marina C
author
Tafrishi, Neda
author
Schuster, Marc
author
Strowig, Till
author
Schmitz, Ingo
author
2021-08-26
Autophagy is an evolutionary conserved catabolic pathway that ensures the degradation of intracellular components. The autophagic pathway is regulated by autophagy-related (Atg) proteins that govern formation of double-membraned vesicles called autophagosomes. Autophagy deficiency in regulatory T (Treg) cells leads to increased apoptosis of these cells and to the development of autoimmune disorders, predominantly characterized by intestinal inflammation. Recently, RORγt-expressing Treg cells have been identified as key regulators of gut homeostasis, preventing intestinal immunopathology. To study the role of autophagy in RORγt+ Foxp3+ Treg cells, we generated mice lacking the essential component of the core autophagy machinery Atg5 in Foxp3+ cells. Atg5 deficiency in Treg cells led to a predominant intestinal inflammation. While Atg5-deficient Treg cells were reduced in peripheral lymphoid organs, the intestinal RORγt+ Foxp3+ subpopulation of Treg cells was most severely affected. Our data indicated that autophagy is essential to maintain the intestinal RORγt+ Foxp3+ Treg population, thereby protecting the mice from gut inflammatory disorders.
Front Immunol. 2021 Aug 26;12:705436. doi: 10.3389/fimmu.2021.705436.
34512629
10.3389/fimmu.2021.705436
http://hdl.handle.net/10033/623082
1664-3224
Frontiers in immunology
Atg5
RORγt+ Foxp3+ Treg cells
autophagy
inflammation
intestinal homeostasis
A Central Role for Atg5 in Microbiota-Dependent Foxp3 RORγt Treg Cell Preservation to Maintain Intestinal Immune Homeostasis.
oai:repository.helmholtz-hzi.de:10033/6231182021-12-14T03:20:36Zcom_10033_128109com_10033_620659col_10033_621771col_10033_128110col_10033_620660
00925njm 22002777a 4500
dc
Formaglio, Pauline
author
Alabdullah, Mohamad
author
Siokis, Anastasios
author
Handschuh, Juliane
author
Sauerland, Ina
author
Fu, Yan
author
Krone, Anna
author
Gintschel, Patricia
author
Stettin, Juliane
author
Heyde, Sandrina
author
Mohr, Juliane
author
Philipsen, Lars
author
Schröder, Anja
author
Robert, Philippe A
author
Zhao, Gang
author
Khailaie, Sahamoddin
author
Dudeck, Anne
author
Bertrand, Jessica
author
Späth, Gerald F
author
Kahlfuß, Sascha
author
Bousso, Philippe
author
Schraven, Burkhart
author
Huehn, Jochen
author
Binder, Sebastian
author
Meyer-Hermann, Michael
author
Müller, Andreas J
author
2021-10-15
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.
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
2-photon microscopy
Leishmania
biosensor
iNOS
inflammation
intracellular pathogen
monocyte
nitric oxide
phagocyte
Nitric oxide controls proliferation of Leishmania major by inhibiting the recruitment of permissive host cells.
oai:repository.helmholtz-hzi.de:10033/6231252021-12-22T01:49:29Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Ruck, Tobias
author
Bock, Stefanie
author
Pfeuffer, Steffen
author
Schroeter, Christina B
author
Cengiz, Derya
author
Marciniak, Paul
author
Lindner, Maren
author
Herrmann, Alexander
author
Liebmann, Marie
author
Kovac, Stjepana
author
Gola, Lukas
author
Rolfes, Leoni
author
Pawlitzki, Marc
author
Opel, Nils
author
Hahn, Tim
author
Dannlowski, Udo
author
Pap, Thomas
author
Luessi, Felix
author
Schreiber, Julian A
author
Wünsch, Bernhard
author
Kuhlmann, Tanja
author
Seebohm, Guiscard
author
Tackenberg, Björn
author
Seja, Patricia
author
Döring, Frank
author
Wischmeyer, Erhard
author
Chasan, Achmet Imam
author
Roth, Johannes
author
Klotz, Luisa
author
Meyer Zu Hörste, Gerd
author
Wiendl, Heinz
author
Marschall, Tobias
author
Floess, Stefan
author
Huehn, Jochen
author
Budde, Thomas
author
Bopp, Tobias
author
Bittner, Stefan
author
Meuth, Sven G
author
2021-10-26
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.
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
K18.1 translates T cell receptor signals into thymic regulatory T cell development.
oai:repository.helmholtz-hzi.de:10033/6231902022-05-11T01:55:48Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Saleh, Reem
author
Sasidharan Nair, Varun
author
Toor, Salman M.
author
Elkord, Eyad
author
2021-08-27
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
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
Acquired resistance
Adoptive T-cell therapy
Cancer
Epigenetics
Immune checkpoint inhibitor
Immunotherapy
Intrinsic resistance
Therapeutic strategies
Tumor microenvironment
Intrinsic and acquired cancer immunotherapy resistance
oai:repository.helmholtz-hzi.de:10033/6231912022-06-11T02:16:12Zcom_10033_128109col_10033_128110
00925njm 22002777a 4500
dc
Song, Mi Hye
author
Gupta, Anupriya
author
Sasidharan Nair, Varun
author
Oh, Kwonik
author
2022-04-25
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.
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
Atopic dermatitis
CD4 T cell +
Challenge
IL-33
MC903
Sensitization
CD4+ T cells play an essential role in chronic MC903-induced skin inflammation