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

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

Author information

1
Department of Cellular Immunology, Clinic for Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
2
German Rheumatism Research Center (DRFZ) Berlin, Leibniz Association, Berlin, Germany.
3
Department of Microbiology and Immunology, University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
4
Molecular Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
5
Research Group Microbial Immune Regulation, Helmholtz Centre for Infection Research, Braunschweig, Germany.
6
Department of Medical Biology, University of Melbourne, Melbourne, Australia.
7
Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
8
Department of Cancer Immunology, Genentech, San Francisco, CA, USA.
9
Department of Bioinformatics and Computational Biology, Genentech, San Francisco, CA, USA.
10
Department of Biochemical and Cellular Pharmacology, Genentech, San Francisco, CA, USA.
11
Sanquin Research, Department of Hematopoiesis and Landsteiner Laboratory, Amsterdam Infection and Immunity Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
12
Medical Department I, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
13
Belozersky Institute of Physico-Chemical Biology and Biological Faculty, M.V. Lomonosov Moscow State University, Moscow, Russia.
14
Department of Cancer Immunology, Genentech, San Francisco, CA, USA. saschar@gene.com.
15
Department of Microbiology and Immunology, University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia. axel.kallies@unimelb.edu.au.
16
Molecular Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia. axel.kallies@unimelb.edu.au.
17
Institute of Immunology, Christian-Albrechts-Universität zu Kiel & Universitätsklinik Schleswig Holstein, Kiel, Germany. alexander.scheffold@uksh.de.

Abstract

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.

PMID:
30778241
DOI:
10.1038/s41590-019-0316-2
[Indexed for MEDLINE]

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