Both microbial and host genetic factors contribute to the pathogenesis of autoimmune diseases1,2,3,4. 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 pathobionts4,5,6. 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.
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NCBI Reference Sequence
Sequence Read Archive
We thank S. Y. Kim and the NYU Rodent Genetic Engineering Laboratory (RGEL) for generating TCR transgenic mice, A. Heguy and colleagues at the NYU School of Medicine’s Genome Technology Center (GTC) for preparation of RNA-seq libraries and RNA sequencing, the NIH Tetramer Core Facility for generating MHC class II tetramers, K. Murphy for providing the 58α−β− hybridoma line, D. E. Levy for providing the Stat3fl/fl;Cd4cre mice, J. Fox for providing the H. hepaticus strain, P. Dash and P. G. Thomas for advice on single-cell TCR cloning, and J. A. Hall, J. Muller and J. Lafaille for suggestions on the manuscript. The Experimental Pathology Research Laboratory of NYU Medical Center is supported by National Institutes of Health Shared Instrumentation grants S10OD010584-01A1 and S10OD018338-01. The GTC is partially supported by the Cancer Center Support grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center. This work was supported by the Irvington Institute fellowship program of the Cancer Research Institute (M.X.); the training program in Immunology and Inflammation 5T32AI100853 (M.P.); the Helen and Martin Kimmel Center for Biology and Medicine (D.R.L.); the Colton Center for Autoimmunity (D.R.L.); and National Institutes of Health grant R01DK103358 (R.B. and D.R.L.). D.R.L. is an Investigator of the Howard Hughes Medical Institute.