c-Maf-dependent Treg cell control of intestinal TH17 cells and IgA establishes host–microbiota homeostasis

Neumann, Christian; Blume, Jonas; Roy, Urmi; Teh, Peggy P; Vasanthakumar, Ajithkumar; Beller, Alexander; Liao, Yang; Heinrich, Frederik; Arenzana, Teresita L.; Hackney, Jason A.; Eidenschenk, Céline; Galvez, Eric; Stehle, Christina; Heinz, Gitta Anne; Maschmeyer, Patrick; Sidwell, Tom; Hu, Yifang; Amsen, Derk; Romagnani, Chiara; Chang, Hyun‐Dong; Kruglov, Andrey; Mashreghi, Mir‐Farzin; Shi, Wei; Strowig, Till; Rutz, Sascha; Kallies, Axel; Scheffold, Alexander

doi:10.1038/s41590-019-0316-2

Cited by 148 publications

(158 citation statements)

References 58 publications

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“…Strikingly, Bach2 fl/fl Foxp3 Cre mice almost completely lacked RORγt + pTreg cells and were largely protected from experimentally induced colitis. This is not only consistent with a critical role of IL-10 in this disease model 36,37 but also in line with our recent observations according to which loss of RORγt + pTreg cells correlated with protection from DSS-induced colitis 38 . In contrast, in adoptive transfer experiments, Bach2-deficient Treg cells showed impaired proliferative capacity and survival compared with control cells.…”

Section: Bach2 Is Required For Of Treg Cell Expansion and Maintenancesupporting

confidence: 92%

“…To test the functional consequences of Bach2 loss in non-lymphoid tissue inflammation, we utilized a model of chemically induced colitis, which is controlled by Treg cells in a manner dependent on the immunomodulatory cytokine IL-10 (refs. [36][37][38]. We administered Bach2 fl/fl Foxp3 Cre and Foxp3 Cre control mice dextran sodium sulfate (DSS) dissolved in drinking water and assessed the resulting colitis.…”

Section: Bach2 Is Required For Of Treg Cell Expansion and Maintenancementioning

confidence: 99%

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Attenuation of TCR-induced transcription by Bach2 controls regulatory T cell differentiation and homeostasis

et al. 2020

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Differentiation and homeostasis of Foxp3 + regulatory T (Treg) cells are strictly controlled by T-cell receptor (TCR) signals; however, molecular mechanisms that govern these processes are incompletely understood. Here we show that Bach2 is an important regulator of Treg cell differentiation and homeostasis downstream of TCR signaling. Bach2 prevents premature differentiation of fully suppressive effector Treg (eTreg) cells, limits IL-10 production and is required for the development of peripherally induced Treg (pTreg) cells in the gastrointestinal tract. Bach2 attenuates TCR signaling-induced IRF4-dependent Treg cell differentiation. Deletion of IRF4 promotes inducible Treg cell differentiation and rescues pTreg cell differentiation in the absence of Bach2. In turn, loss of Bach2 normalizes eTreg cell differentiation of IRF4-deficient Treg cells. Mechanistically, Bach2 counteracts the DNA-binding activity of IRF4 and limits chromatin accessibility, thereby attenuating IRF4-dependent transcription. Thus, Bach2 balances TCR signaling induced transcriptional activity of IRF4 to maintain homeostasis of thymically-derived and peripherally-derived Treg cells.

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Section: Bach2 Is Required For Of Treg Cell Expansion and Maintenancesupporting

confidence: 92%

Section: Bach2 Is Required For Of Treg Cell Expansion and Maintenancementioning

confidence: 99%

Attenuation of TCR-induced transcription by Bach2 controls regulatory T cell differentiation and homeostasis

et al. 2020

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“…We show herein that multiple signaling pathways cooperate to exert both positive and negative control over RORγt + expression by Tregs. We confirmed and extended previous data showing that transcription factor c-Maf plays a major role for the acquisition of RORγt expression by Tregs (8,12,31). However, contrary to RORγt, which is confined to a subset of intestinal Tregs, c-Maf expression is found in a wider proportion of Tregs, located in distinct organs.…”

Section: Discussionsupporting

confidence: 90%

Multiple Environmental Signaling Pathways Control the Differentiation of RORγt-Expressing Regulatory T Cells

et al. 2020

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RORγt-expressing Tregs form a specialized subset of intestinal CD4 + Foxp3 + cells which is essential to maintain gut homeostasis and tolerance to commensal microbiota. Recently, c-Maf emerged as a critical factor in the regulation of RORγt expression in Tregs. However, aside from c-Maf signaling, the signaling pathways involved in the differentiation of RORγt + Tregs and their possible interplay with c-Maf in this process are largely unknown. We show that RORγt + Treg development is controled by positive as well as negative signals. Along with c-Maf signaling, signals derived from a complex microbiota, as well as IL-6/STAT3-and TGF-β-derived signals act in favor of RORγt + Treg development. Ectopic expression of c-Maf did not rescue RORγt expression in STAT3-deficient Tregs, indicating the presence of additional effectors downstream of STAT3. Moreover, we show that an inflammatory IFN-γ/STAT1 signaling pathway acts as a negative regulator of RORγt + Treg differentiation in a c-Maf independent fashion. These data thus argue for a complex integrative signaling network that finely tunes RORγt expression in Tregs. The finding that type 1 inflammation impedes RORγt + Treg development even in the presence of an active IL-6/STAT3 pathway further suggests a dominant negative effect of STAT1 over STAT3 in this process.

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“…S4 C). In contrast, the expression of c-Maf, which has recently been shown to be important for RORγ + Treg cell differentiation (Xu et al, 2018;Neumann et al, 2019;Wheaton et al, 2017), did not change with age ( Fig. 8 D).…”

Section: Why Can't Tconv Cells From Infant Mice Give Rise To Rorγ + Tmentioning

confidence: 81%

Developmental and cellular age direct conversion of CD4+ T cells into RORγ+ or Helios+ colon Treg cells

Pratama

Schnell

Mathis

et al. 2019

Journal of Experimental Medicine

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RORγ+ and Helios+ Treg cells in the colon are phenotypically and functionally distinct, but their origins and relationships are poorly understood. In monocolonized and normal mice, single-cell RNA-seq revealed sharing of TCR clonotypes between these Treg cell populations, potentially denoting a common progenitor. In a polyclonal Treg cell replacement system, naive conventional CD4+ (Tconv) cells, but not pre-existing tTregs, could differentiate into RORγ+ pTregs upon interaction with gut microbiota. A smaller proportion of Tconv cells converted into Helios+ pTreg cells, but these dominated when the Tconv cells originated from preweaning mice. T cells from infant mice were predominantly immature, insensitive to RORγ-inducing bacterial cues and to IL6, and showed evidence of higher TCR-transmitted signals, which are also characteristics of recent thymic emigrants (RTEs). Correspondingly, transfer of adult RTEs or Nur77high Tconv cells mainly yielded Helios+ pTreg cells, recapitulating the infant/adult difference. Thus, CD4+ Tconv cells can differentiate into both RORγ+ and Helios+ pTreg cells, providing a physiological adaptation of colonic Treg cells as a function of the age of the cell or of the individual.

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c-Maf-dependent Treg cell control of intestinal TH17 cells and IgA establishes host–microbiota homeostasis

Cited by 148 publications

References 58 publications

Attenuation of TCR-induced transcription by Bach2 controls regulatory T cell differentiation and homeostasis

Attenuation of TCR-induced transcription by Bach2 controls regulatory T cell differentiation and homeostasis

Multiple Environmental Signaling Pathways Control the Differentiation of RORγt-Expressing Regulatory T Cells

Developmental and cellular age direct conversion of CD4+ T cells into RORγ+ or Helios+ colon Treg cells

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