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

Abstract

Foxp3⁺ regulatory T cells (T_reg cells) are crucial for the maintenance of immune homeostasis both in lymphoid tissues and in non-lymphoid tissues. Here we demonstrate that the ability of intestinal T_reg cells to constrain microbiota-dependent interleukin (IL)-17-producing helper T cell (T_H17 cell) and immunoglobulin A responses critically required expression of the transcription factor c-Maf. The terminal differentiation and function of several intestinal T_reg cell populations, including RORγt⁺ T_reg cells and follicular regulatory T cells, were c-Maf dependent. c-Maf controlled T_reg cell-derived IL-10 production and prevented excessive signaling via the kinases PI(3)K (phosphatidylinositol-3-OH kinase) and Akt and the metabolic checkpoint kinase complex mTORC1 (mammalian target of rapamycin) and expression of inflammatory cytokines in intestinal T_reg cells. c-Maf deficiency in T_reg cells led to profound dysbiosis of the intestinal microbiota, which when transferred to germ-free mice was sufficient to induce exacerbated intestinal T_H17 responses, even in a c-Maf-competent environment. Thus, c-Maf acts to preserve the identity and function of intestinal T_reg cells, which is essential for the establishment of host-microbe symbiosis.