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.

炎症性肠病 (IBD) 是由致病性 T 细胞驱动的多因素慢性肠道炎症，其中很大一部分患者对当前的抗炎方案有抵抗力。结肠炎致病性和耐药性的潜在机制尚不完全清楚。在这里，我们证明 RORα 在活动性 UC 患者中高度表达，特别是在那些对抗 TNF 治疗无反应的患者中。CD4 ⁺ Rorα缺乏T 细胞大大减少了结肠炎的发展。从机制上讲，RORα 调节结肠中的 T 细胞浸润并抑制 T 细胞凋亡。同时，全基因组占有率和转录组分析显示 RORα 促进了 mTORC1 的激活。mTORC1 信号在活动性 UC 患者中也过度激活，是 T 细胞介导的结肠炎所必需的。因此，我们的结果证明了 RORα-mTORC1 轴在 CD4 ⁺ T 细胞中在促进 IBD 中的关键作用，这可能是针对人类患者的。