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

The transcription factor c-MAF is required for the generation of Helicobacter -specific regulatory T cells that selectively restrain pro-inflammatory T H 17 cells; the absence of c-MAF in mouse regulatory T cells results in pathobiont-dependent inflammatory bowel disease. Tolerance mechanism against a gut commensal pathobiont Some common commensal gut bacteria that can cause spontaneous colitis—chronic inflammation in the colon—in susceptible individuals are well tolerated in others, but the reason for this difference is unclear. In this paper, the authors show that, in mice, the transcription factor c-MAF is required for the generation of Helicobacter -specific regulatory T (T reg ) cells, which selectively retrain Helicobacter -specific pro-inflammatory T helper 17 (T H 17) cells. In the absence of c-MAF or the c-MAF-induced cytokine IL-10, the bacterial-specific T reg –T H 17 balance becomes impaired, and the animals develop pathobiont-dependent inflammatory bowel disease. The authors suggest that engineering non-pathogenic T reg -cell-inducing microbes that express pathobiont antigens could be a therapeutic approach to re-establishing homeostatic conditions in patients with inflammatory bowel disease, reducing the effects of the disease. Both microbial and host genetic factors contribute to the pathogenesis of autoimmune diseases 1 , 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 pathobionts 4 , 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 (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 RORγt-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 cel