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Nature. 2018 Feb 15;554(7692):373-377. doi: 10.1038/nature25500. Epub 2018 Feb 7.

c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont.

Author information

1
Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.
2
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York 14642, USA.
3
Courant Institute of Mathematical Sciences, Computer Science Department, New York University, New York, New York 10003, USA.
4
The Howard Hughes Medical Institute, New York University School of Medicine, New York, New York 10016, USA.
5
Mucosal Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland 20892, USA.
6
NIAID Microbiome Program, NIH, Bethesda, Maryland 20892, USA.
7
Center for Genomics and Systems Biology, Department of Biology, New York University, New York, New York 10003, USA.
8
Center for Computational Biology, Flatiron Institute, Simons Foundation, New York, New York 10010, USA.

Abstract

Both microbial and host genetic factors contribute to the pathogenesis of autoimmune diseases. There is accumulating evidence that microbial species that potentiate chronic inflammation, as in inflammatory bowel disease, often also colonize healthy individuals. These microorganisms, including the Helicobacter species, can induce pathogenic T cells and are collectively referred to as pathobionts. However, how such T cells are constrained in healthy individuals is not yet understood. Here we report that host tolerance to a potentially pathogenic bacterium, Helicobacter hepaticus, is mediated by the induction of RORγt+FOXP3+ regulatory T (iTreg) cells that selectively restrain pro-inflammatory T helper 17 (TH17) cells and whose function is dependent on the transcription factor c-MAF. Whereas colonization of wild-type mice by H. hepaticus promoted differentiation of RORγt-expressing microorganism-specific iTreg cells in the large intestine, in disease-susceptible IL-10-deficient mice, there was instead expansion of colitogenic TH17 cells. Inactivation of c-MAF in the Treg cell compartment impaired differentiation and function, including IL-10 production, of bacteria-specific iTreg cells, and resulted in the accumulation of H. hepaticus-specific inflammatory TH17 cells and spontaneous colitis. By contrast, RORγt inactivation in Treg cells had only a minor effect on the bacteria-specific Treg and TH17 cell balance, and did not result in inflammation. Our results suggest that pathobiont-dependent inflammatory bowel disease is driven by microbiota-reactive T cells that have escaped this c-MAF-dependent mechanism of iTreg-TH17 homeostasis.

PMID:
29414937
PMCID:
PMC5814346
DOI:
10.1038/nature25500
[Indexed for MEDLINE]
Free PMC Article

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