RORα is critical for mTORC1 activity in T cell-mediated colitis.

Inflammatory bowel disease (IBD) is multi-factorial chronic intestinal inflammation driven by pathogenic T cells, among which a large portion of patients are resistant to current anti-inflammatory regimes. The mechanisms underlying colitis pathogenicity and drug resistance are not fully understood. Here, we demonstrate that RORα is highly expressed in active UC patients, particularly in those non-responsive to anti-TNF treatment. Rorα deficiency in CD4+ T cells greatly reduced colitis development. Mechanistically, RORα regulated T cell infiltration in colon and inhibited T cell apoptosis. Meanwhile, genome-wide occupancy and transcriptome analysis revealed that RORα promoted mTORC1 activation. mTORC1 signaling, also hyperactivated in active UC patients, is necessary for T cell-mediated colitis. Our results thus demonstrate a crucial role of the RORα-mTORC1 axis in CD4+ T cells in promoting IBD, which may be targeted in human patients.