c-Maf-dependent Treg cell control of intestinal TH17 cells and IgA establishes host–microbiota homeostasis. 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. In peripheral tissues, Treg cells acquire enhanced suppressive functions and co-opt distinct transcriptional modules, allowing context and tissue-dependent immune regulation. Here we show that the transcription factor c-Maf was highly expressed by effector Treg cells and controlled their IL-10 production. In the intestine, c-Maf was required for the differentiation of RORgt+ microbiota-dependent Treg cells, and restricted their production of inflammatory cytokines. Consequently, Treg cell-specific loss of c-Maf resulted in perturbed intestinal homeostasis, microbial dysbiosis and a selective failure to control Th17 responses during homeostasis and upon chemically induced epithelial damage. Molecular profiling revealed that c-Maf regulated expression of key genes of the transcriptional signature of intestinal Treg cells, including Rorc and Il10. Thus, our study identifies a key role of c-Maf in preserving the identity and function of intestinal Treg cells, essential for the control of intestinal immune homeostasis. Overall design: Transcriptional profiling of control (Foxp3Cre-YFP, "WT") and Maf-KO (Maffl/fl x Foxp3Cre-YFP, "KO") Treg cells sorted from Gut and Spleen