Journal
NATURE IMMUNOLOGY
Volume 20, Issue 4, Pages 471-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41590-019-0316-2
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Funding
- Deutsche Forschungsgemeinschaft (DFG) under Germany's Excellence Strategy-EXC [2167-390884018, SFB650, CRC/TR 241]
- German Federal Ministry of Education and Science (BMBF)-Project InfectControl 2020 Projekt DIAT [FKZ: 03ZZ0827A]
- state of Berlin
- 'European Regional Development Fund' ERDF 2014-2020 [EFRE 1.8/11]
- Helmholtz Association [VH-NG-933]
- National Health and Medical Research Council (NHMRC) [1069075, 1106378]
- Sylvia and Charles Viertel Foundation
- Walter and Eliza Institute Centenary Fellowship - CSL
- Deutsche Forschungsgemeinschaft
- National Health and Medical Research Council of Australia [1069075, 1106378] Funding Source: NHMRC
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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(H)17 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 ROR gamma t(+) 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(H)17 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.
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