Multiple environmental signaling pathways control the differentiation of RORγt-expressing regulatory T cells

Abstract

ROR{gamma}t-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 ROR{gamma}t expression in Tregs. However, aside from c-Maf signaling, the signaling pathways involved in the differentiation of ROR{gamma}t+ Tregs and their possible interplay with c-Maf in this process are largely unknown. We show that ROR{gamma}t+ Treg development is controlled 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-{beta}-derived signals act in favor of ROR{gamma}t+ Treg development. Ectopic expression of c-Maf did not rescue ROR{gamma}t expression in STAT3-deficient Tregs, indicating the presence of additional effectors downstream of STAT3. Moreover, we show that an inflammatory IFN-{gamma}/STAT1 signaling pathway acts as a negative regulator of ROR{gamma}t+ Treg differentiation in a c-Maf independent fashion.\n\nThese data thus argue for a complex integrative signaling network that finely tunes ROR{gamma}t expression in Tregs. The finding that type 1 inflammation impedes ROR{gamma}t+ 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.