An epigenetic polarity governing T cell tolerance for commensal microbiota 2250947
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. 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. 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. 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. National Institute of Allergy and Infectious Diseases Immune Response Regulation: Molecular Mechanisms (IRM)