炎症性肠病（Inflammatory Bowel Diseases, IBD）主要由克罗恩病（Chron’s Disease, CD）和溃疡性结肠炎（Ulcerative Disease, UC）组成，是由环境诱因、遗传易感性、免疫失调和肠道微生物紊乱等多种因素共同引起的肠道系统慢性炎症，并伴有多种并发症，对患者的寿命和生活质量造成极大影响。炎症性肠病的发病率在全球范围内逐年升高，影响数百万人口。TNF拮抗药物是目前针对中重症患者使用最多的生物制剂，具有优异的疗效，然而20-40%的患者对药物具有抗性。目前为止，炎症性肠病的发病机制、TNF拮抗药物的作用机制以及药物敏感性机制，均不是十分清楚。 作为一类慢性炎症性自身免疫疾病，淋巴细胞的异常扩增和功能失调对肠道炎症的发生发展至关重要。在活动期患者中常能观察到CD4+ T淋巴细胞的增多，小鼠模型中CD4+ T淋巴细胞具有很强的肠炎致病性，在临床中阻断淋巴细胞向肠道的归巢也具有很好的疗效，说明CD4+ T淋巴细胞在诱导肠炎发生中发挥关键作用。此前，在克罗恩病中，研究发现T细胞在抗TNF治疗抵抗的患者中有独特的细胞转录特征，且表达IL-17A和IL-23R的T细胞在抗TNF治疗抵抗的患者中显著增加，暗示T细胞特别是Th17细胞，可能参与抗TNF药物敏感性的调控。因此，本课题致力于探究肠道炎症中的免疫调控机制，特别是抗TNF药物敏感性相关基因，以了解疾病的发生发展并寻找新的药物靶点。我们发现调控Th17细胞的关键转录因子RORA，在活动期溃疡性结肠炎患者，尤其是在对抗TNF治疗无反应患者药物治疗前的活检组织中显著高表达。利用T细胞转移性小鼠肠炎模型，我们发现在CD4+ T细胞中敲除Rorα，能显著缓解小鼠肠炎的严重程度。机制方面，RORα促进肠系膜淋巴结中T细胞向大肠的归巢并抑制肠道T细胞凋亡，进而促进T细胞在肠道的浸润。同时，RORα调控CD4+ T细胞效应性细胞因子的分泌并促进其致病性，并能促进mTORC1信号通路的激活。我们进一步发现，活动期溃疡性结肠炎患者中mTORC1信号转导也异常活跃，且CD4+ T细胞在转移性小鼠肠炎模型中的致病性，依赖于mTORC1。因此，我们的结果证明了RORα-mTORC1轴在调控CD4+ T细胞促进肠炎中的关键作用，可能为炎症性肠病的治疗提供了新的靶点。
Inflammatory Bowel Diseases （IBD）, composed of Crohn’s Disease （CD） and Ulcerative Disease （UC）, is multi-factorial chronic gastrointestinal inflammation driven by environmental triggers, genetic susceptibility, immune system dysfunction, and change of gut microbiota. IBD is accompanied by a variety of complications, and greatly affects the lifespan and the quality of life. The incidence of IBD is increasing worldwide, affecting millions of people. Currently, anti-TNF antibodies are the mainstream biological agents for patients with moderate to severe illness, and have excellent curative effects. However, 20-40% of patients are primary non-responsive to anti-TNF treatment. So far, the pathogenesis of IBD, the mechanisms of anti-TNF treatment and anti-TNF therapy responsiveness are not fully understood.Increased CD4＋ T lymphocytes was observed in active IBD patients, and the pathogenicity of CD4＋ T lymphocytes in mouse models have been confirmed. Besides, blocking gut-homing receptors on T cells have beneficial effects in clinical trials. These researches indicated an essential role of CD4＋ T cells in inducing gut inflammation. In addition, researchers also found that in anti-TNF treatment non-responders, T cells, especially cells expressing IL-17A and IL-23R, significantly increased, suggesting that T cells, especially Th17 cells, may be involved in the regulation of anti-TNF therapy responsiveness. Therefore, we aimed to investigate the pathogenic regulators of colitis, especially those related to anti-TNF treatment responsiveness, to further understand the mechanism of gut inflammation and find potential drug targets.We found that the transcription of RORA, the key transcription factor that regulates Th17 cells development, was significantly increased in the mucosal biopsies obtained from active ulcerative colitis patients, especially in those who are resistant to anti-TNF therapy before treatment. Using the T cell transfer colitis model, we found that Rorα deficiency in CD4＋ T cells significantly ameliorated the disease severity. Mechanistically, RORα promoted T cell infiltration in the large intestine by promoting gut-homing receptors expression on T cells and inhibiting colonic T cells apoptosis. Meanwhile, RORα regulated the expression of effector cytokines and promoted CD4＋ T cells pathogenicity. Moreover, the fully activation of mTORC1 signaling dependent on RORα. mTORC1 signal transduction was hyper-activated in active ulcerative colitis patients, and CD4＋ T cells pathogenicity in driving colitis also depended on mTORC1 activation. 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.
