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 ROR alpha is highly expressed in active UC patients, particularly in those non-responsive to anti-TNF treatment. Ror alpha deficiency in CD4(+) T cells greatly reduced colitis development. Mechanistically, ROR alpha regulated T cell infiltration in colon and inhibited T cell apoptosis. Meanwhile, genome-wide occupancy and transcriptome analysis revealed that RORa 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 ROR alpha-mTORC1 axis in CD4(+) T cells in promoting IBD, which may be targeted in human patients.

Automated summary

The study found that RORα is highly expressed in active UC patients, especially in those non-responsive to anti-TNF treatment. RORα plays a crucial role in promoting IBD development in CD4(+) T cells by regulating T cell infiltration, inhibiting T cell apoptosis, and promoting mTORC1 activation. This indicates that the RORα-mTORC1 axis may be a potential therapeutic target for human patients with IBD.