Class Ib MHC-Mediated Immune Interactions Play a Critical Role in Maintaining Mucosal Homeostasis in the Mammalian...

Lymphocytes within the intestinal epithelial layer (IEL) in mammals have unique composition compared with their counterparts in the lamina propria. Little is known about the role of some of the key colonic IEL subsets, such as TCRαβ⁺CD8⁺ T cells, in inflammation. We have recently described liver-enriched innate-like TCRαβ⁺CD8αα regulatory T cells, partly controlled by the non-classical MHC molecule, Qa-1^b, that upon adoptive transfer protect from T cell-induced colitis. In this study, we found that TCRαβ⁺CD8αα T cells are reduced among the colonic IEL during inflammation, and that their activation with an agonistic peptide leads to significant Qa-1^b-dependent protection in an acute model of colitis. Cellular expression of Qa-1^b during inflammation and corresponding dependency in peptide-mediated protection suggest that Batf3-dependent CD103⁺CD11b^- type 1 conventional dendritic cells control the protective function of TCRαβ⁺CD8αα T cells in the colonic epithelium. In the colitis model, expression of the potential barrier-protective gene, Muc2, is enhanced upon administration of a Qa-1b agonistic peptide. Notably, in steady state, the mucin metabolizing Akkermansia muciniphila was found in significantly lower abundance amid a dramatic change in overall microbiome and metabolome, increased IL-6 in explant culture, and enhanced sensitivity to dextran sulfate sodium in Qa-1b deficiency. Finally, in patients with inflammatory bowel disease, we found upregulation of HLA-E, a Qa-1^b analog with inflammation and biologic non-response, in silico, suggesting the importance of this regulatory mechanism across species.