Intestinal epithelial MHC class II induces encephalitogenic CD4 T cells and initiates central nervous system autoimmunity.

The intestinal epithelium plays a critical role in immune-microbiota interactions, yet its contribution to systemic autoimmunity remains unclear. Here, we identify intestinal epithelial cells (IECs) as initiators of experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS). In both EAE mice and patients with MS, IECs up-regulate antigen presentation pathways and are associated with increased intestinal T helper 17 (TH17) cell accumulation. Epithelial major histocompatibility complex class II (MHC II) was highly expressed during EAE, particularly in the ileum, and its conditional deletion reduced pathogenic TH17 cell generation and disease severity. Using parabiosis and photoconversion models, we demonstrate that TH17 cells induced in the intestinal lamina propria migrate to the spinal cord. Functional coculture assays showed that IEC organoids with cognate myelin oligodendrocyte glycoprotein antigen induce RORγt+CD4+ T cell differentiation in an MHC II-dependent manner. These findings uncover a conserved gut-central nervous system axis in autoimmunity and position epithelial antigen presentation as a key initiator of neuroinflammation.