TY - JOUR
T1 - c-Maf-dependent Treg cell control of intestinal TH17 cells and IgA establishes host-microbiota homeostasis
AU - Neumann, Christian
AU - Blume, Jonas
AU - Roy, Urmi
AU - Teh, Peggy P
AU - Vasanthakumar, Ajithkumar
AU - Beller, Alexander
AU - Liao, Yang
AU - Heinrich, Frederik
AU - Arenzana, Teresita L
AU - Hackney, Jason A
AU - Eidenschenk, Celine
AU - Gálvez, Eric J C
AU - Stehle, Christina
AU - Heinz, Gitta A
AU - Maschmeyer, Patrick
AU - Sidwell, Tom
AU - Hu, Yifang
AU - Amsen, Derk
AU - Romagnani, Chiara
AU - Chang, Hyun-Dong
AU - Kruglov, Andrey
AU - Mashreghi, Mir-Farzin
AU - Shi, Wei
AU - Strowig, Till
AU - Rutz, Sascha
AU - Kallies, Axel
AU - Scheffold, Alexander
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
KW - Animals
KW - Cells, Cultured
KW - Colitis/immunology
KW - Cytokines/metabolism
KW - Dysbiosis
KW - Gene Expression Regulation
KW - Homeostasis
KW - Immunoglobulin A/biosynthesis
KW - Interleukin-10/biosynthesis
KW - Intestines/immunology
KW - Mice, Inbred C57BL
KW - Microbiota
KW - Proto-Oncogene Proteins c-maf/genetics
KW - T-Lymphocytes, Regulatory/enzymology
KW - Th17 Cells/immunology
UR - http://www.scopus.com/inward/record.url?scp=85061712972&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41590-019-0316-2
DO - https://doi.org/10.1038/s41590-019-0316-2
M3 - Article
C2 - 30778241
SN - 1529-2908
VL - 20
SP - 471
EP - 481
JO - Nature immunology
JF - Nature immunology
IS - 4
ER -