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

Both microbial and host genetic factors contribute to the pathogenesis of autoimmune diseases(1-4). 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 pathobionts(4-6). 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 ROR gamma t(+)FOXP3(+) regulatory T (iT(reg)) cells that selectively restrain pro-inflammatory T helper 17 (T(H)17) cells and whose function is dependent on the transcription factor c-MAF. Whereas colonization of wild-type mice by H. hepaticus promoted differentiation of ROR gamma t-expressing microorganism-specific iT(reg) cells in the large intestine, in disease-susceptible IL-10-deficient mice, there was instead expansion of colitogenic T(H)17 cells. Inactivation of c-MAF in the T-reg cell compartment impaired differentiation and function, including IL-10 production, of bacteria-specific iT(reg) cells, and resulted in the accumulation of H. hepaticus-specific inflammatory T(H)17 cells and spontaneous colitis. By contrast, ROR gamma t inactivation in T-reg cells had only a minor effect on the bacteria-specific T-reg and T(H)17 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 iT(reg)-T(H)17 homeostasis.