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

Abstract

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.

Maternal Lactobacillus rhamnosus administration impacts neonatal CD4 T-cell activation and prevents murine T helper 2-type allergic airways disease

“…However, the probiotic was responsible for a significant induction of RORγt + Foxp3 + Treg within the MLN. These RORγt + Treg were initially described in the draining lymph nodes from the intestine ( 50 , 51 ). This Treg subset is negatively regulated by Th1 cells ( 42 ) but it remains elusive which cDC regulate its differentiation.…”

The Many Functions of Foxp3+ Regulatory T Cells in the Intestine

“…In accordance with the fact that expression of c-Maf (and RORgt) in Treg cells is dependent on STAT3 activation (15,32,35), uncontrolled intestinal Th17 cell responses and spontaneous colitis were also detected in Treg cell-specific STAT3-deficient mice (36). In addition to c-Maf, RORgt + pTreg cells also co-express high levels of the transcription factor Blimp-1 (37).…”

c-MAF, a Swiss Army Knife for Tolerance in Lymphocytes

“…Strikingly, a large proportion, ranging from 60 to 80%, of Foxp3 + Tregs express c-Maf in the gut (38,(96)(97)(98)(99). In lymphoid organs, c-Maf expression is restricted to effector Tregs (eTreg), which express high levels of CD44 and low levels of CD62L (96,98,99). c-Maf expression is also induced when naïve Tregs are stimulated in vitro with anti-CD3 and anti-CD28 antibodies (96).…”

“…This subset of peripherally induced Tregs has been shown to efficiently protect from intestinal immunopathology in different colitis models (101,102) and to mediate immunological tolerance to the gut pathobiont Helicobacter hepaticus (38). RORγt + Tregs express high levels of c-Maf and genetic ablation of c-Maf leads to a severe defect in the development of this subset (38,(96)(97)(98)(99).…”