c-Maf-dependent T.sub.reg cell control of intestinal T.sub.H17 cells and IgA establishes host-microbiota homeostasis

• Published in: Nature immunology Vol. 20; no. 4; p. 471
• Main Authors: Neumann, Christian, Blume, Jonas, Roy, Urmi, Teh, Peggy P, Vasanthakumar, Ajithkumar, Beller, Alexander, Liao, Yang
• Format: Journal Article
• Language: English
• Published: Nature Publishing Group 01.04.2019
• Subjects: Analysis; Cellular signal transduction; Gene expression; Homeostasis; Immune system; Immunoglobulin A; Immunoglobulins; Interleukins; Microbiota (Symbiotic organisms); Phospholipids; T cells
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/s41590-019-0316-2

Foxp3.sup.+ regulatory T cells (T.sub.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.sub.reg cells to constrain microbiota-dependent interleukin (IL)-17-producing helper T cell (T.sub.H17 cell) and immunoglobulin A responses critically required expression of the transcription factor c-Maf. The terminal differentiation and function of several intestinal T.sub.reg cell populations, including ROR[gamma]t.sup.+ T.sub.reg cells and follicular regulatory T cells, were c-Maf dependent. c-Maf controlled T.sub.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.sub.reg cells. c-Maf deficiency in T.sub.reg cells led to profound dysbiosis of the intestinal microbiota, which when transferred to germ-free mice was sufficient to induce exacerbated intestinal T.sub.H17 responses, even in a c-Maf-competent environment. Thus, c-Maf acts to preserve the identity and function of intestinal T.sub.reg cells, which is essential for the establishment of host-microbe symbiosis.