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

Foxp3+ regulatory T (Treg) cells are essential for immunological tolerance and homeostasis. Upon activation, Treg cells acquire an effector Treg phenotype associated with enhanced suppressive functions, such as the ability to produce IL-10, and co-opt distinct transcriptional modules, allowing context- and tissue-dependent immune regulation. The molecular mediators underlying this process are incompletely understood.Here, we show that the transcription factor c-Maf was highly expressed by effector Treg cells and required for their IL-10 production. In the intestine, c-Maf deficiency within the Treg cell compartment resulted in perturbed immune homeostasis, as evidenced by a selective failure to control intestinal Th17 cells, and microbial dysbiosis. DSS-mediated insult to the intestinal epithelium further enhanced IL-17A and IL-22 responses in Treg-specific c-Maf-deficient mice but surprisingly resulted in protection from DSS colitis. Molecular profiling revealed that c-Maf regulated the expression of key genes of the transcriptional signature of intestinal Treg cells. In particular, c-Maf was required for RORgt expression by microbiota-dependent Treg cells. The high expression of c-Maf in gut-resident Treg cells was maintained by Notch signals. Thus, our study identifies c-Maf as a key regulator of Treg cell-derived IL-10 expression and effector Treg cell differentiation, essential for the control of intestinal immune homeostasis.