An epigenetic polarity governing T cell tolerance for commensal microbiota 2250947

Introduction T cells differentiate into subtypes to maintain immune tolerance or mount inflammatory response upon antigen stimulation. This raises questions about whether and how T cell subtypes rely on fundamentally distinct epigenetic programs. Methods Using Wdr82, a component of the Set1/COMPASS histone H3K4 methyltransferase complex, as a model, we discover that this pathway is broadly required for the activation and function of both Te and Treg cells. Results Counterintuitively, T cell-specific deletion of Wdr82 leads to Te activation and lethal spontaneous colitis. This dysregulation is nearly completely prevented by microbiome depletion or wild-type Treg transfer. Mechanistically, Set1/COMPASS complex interacts with Foxp3 in a TCR-signaling dependent manner. H3K4me3 pathway is preferentially required for Treg induction and for the expression of Treg functional genes such as Il10 and Rorc. Conclusion Thus, the generic H3K4me3 pathway plays a biased role in Treg-dependent immune homeostasis particularly in the presence of commensal microbiota. Our study depicts an epigenetic polarity governing Treg-mediated immune tolerance, highlighting a fundamental asymmetry at the epigenetic level that differentially regulates Treg and conventional T cells. Perturbation of this asymmetry by genetic and environmental factors would lead to autoimmune dysregulation.