Intestinal Epithelial MHC-II at the Interface of Microbiota, Immunity, and Inflammation

Major histocompatibility complex class II (MHC-II) expression by intestinal epithelial cells (IECs) has emerged as a critical mechanism regulating mucosal immune homeostasis at the interface between the intestinal microbiota, epithelial barrier, and immune system. Beyond professional antigen-presenting cells, IEC-intrinsic MHC-II shapes CD4+ T-cell responses, influencing tolerance to commensal microorganisms, immunity to enteric pathogens, and maintenance of barrier integrity. Recent studies have revealed that epithelial MHC-II expression is dynamically regulated by cytokines, the gut microbiota, dietary factors, and microbiota-derived metabolites, linking environmental signals to local adaptive immune responses. Dysregulation of epithelial antigen presentation has been implicated in chronic intestinal inflammation, including inflammatory bowel disease (IBD). This review summarizes current knowledge regarding the molecular regulation, spatial organization, and immunological functions of epithelial MHC-II and discusses its emerging role in host–microbiota interactions, mucosal barrier homeostasis, and intestinal disease.