Intestinal epithelial MHC class II regulation by HDAC3 instructs microbiota-specific CD4+ T cells

Aberrant immune responses to resident microbes promote inflammatory bowel disease and other chronic inflammatory conditions. However, how microbiota-specific immunity is controlled in mucosal tissues remains poorly understood. Here, we find that mice lacking epithelial expression of microbiota-sensitive histone deacetylase 3 (HDAC3) exhibit increased accumulation of commensal-specific CD4+ T cells in the intestine, provoking the hypothesis that epithelial HDAC3 may instruct local microbiota-specific immunity. Consistent with this, microbiota-specific CD4+ T cells and epithelial HDAC3 expression were concurrently induced following early-life microbiota colonization. Further, epithelial-intrinsic ablation of HDAC3 promoted T cell driven-colitis and primed development of pathogenic commensal-specific Th17 cells. Mechanistically, HDAC3 was essential for MHC class II (MHCII) expression by the intestinal epithelium, and epithelial-intrinsic MHCII actively limited commensal-specific Th17 cells and prevented microbiota-triggered inflammation. Remarkably, HDAC3 enabled the microbiota to induce MHCII on epithelial cells and limit the number of commensal-specific T cells in the intestine. Collectively, these data reveal a central role for an epithelial histone deacetylase in controlling development of tissue-intrinsic T cells that recognize commensal microbes and drive pathologic inflammation.