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

Nat Immunol. 2019 Apr;20(4):471-481. doi: 10.1038/s41590-019-0316-2. Epub 2019 Feb 18.


Foxp3+ regulatory T cells (Treg 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 Treg cells to constrain microbiota-dependent interleukin (IL)-17-producing helper T cell (TH17 cell) and immunoglobulin A responses critically required expression of the transcription factor c-Maf. The terminal differentiation and function of several intestinal Treg cell populations, including RORγt+ Treg cells and follicular regulatory T cells, were c-Maf dependent. c-Maf controlled Treg 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 Treg cells. c-Maf deficiency in Treg cells led to profound dysbiosis of the intestinal microbiota, which when transferred to germ-free mice was sufficient to induce exacerbated intestinal TH17 responses, even in a c-Maf-competent environment. Thus, c-Maf acts to preserve the identity and function of intestinal Treg cells, which is essential for the establishment of host-microbe symbiosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Colitis / immunology
  • Cytokines / metabolism
  • Dysbiosis
  • Gene Expression Regulation
  • Homeostasis
  • Immunoglobulin A / biosynthesis*
  • Interleukin-10 / biosynthesis
  • Intestines / immunology*
  • Mice, Inbred C57BL
  • Microbiota*
  • Proto-Oncogene Proteins c-maf / genetics
  • Proto-Oncogene Proteins c-maf / metabolism
  • Proto-Oncogene Proteins c-maf / physiology*
  • T-Lymphocytes, Regulatory / enzymology
  • T-Lymphocytes, Regulatory / immunology*
  • Th17 Cells / immunology*


  • Cytokines
  • Immunoglobulin A
  • Maf protein, mouse
  • Proto-Oncogene Proteins c-maf
  • Interleukin-10