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 disease(1–4). Accumulating evidence suggests that microbial species that potentiate chronic inflammation, as in inflammatory bowel disease (IBD), often also colonize healthy individuals. These microbes, including the Helicobacter species, have the propensity to induce pathogenic T cells and are collectively referred to as pathobionts(4–6). However, an understanding of how such T cells are constrained in healthy individuals is lacking. Here we report that host tolerance to a potentially pathogenic bacterium, Helicobacter hepaticus (H. hepaticus), is mediated by induction of RORγt(+)Foxp3(+) regulatory T cells (iT(reg)) that selectively restrain pro-inflammatory T(H)17 cells and whose function is dependent on the transcription factor c-Maf. Whereas H. hepaticus colonization of wild-type mice promoted differentiation of RORγt-expressing microbe-specific iT(reg) in the large intestine, in disease-susceptible IL-10-deficient animals there was instead expansion of colitogenic T(H)17 cells. Inactivation of c-Maf in the T(reg) compartment likewise impaired differentiation and function, including IL-10 production, of bacteria-specific iT(reg), resulting in accumulation of H. hepaticus-specific inflammatory T(H)17 cells and spontaneous colitis. In contrast, RORγt inactivation in T(reg) only had a minor effect on bacterial-specific T(reg)-T(H)17 balance, and did not result in inflammation. Our results suggest that pathobiont-dependent IBD is driven by microbiota-reactive T cells that have escaped this c-Maf-dependent mechanism of iT(reg)-T(H)17 homeostasis.