Center for IBD Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Department of Gastroenterology, First People's Hospital of Shangqiu City Affiliated to Xinxiang Medical University, Shangqiu, China.
Cell Mol Gastroenterol Hepatol. 2022;13(4):1201-1221. doi: 10.1016/j.jcmgh.2021.12.007. Epub 2021 Dec 14.
BACKGROUND & AIMS: TOB1 is an anti-proliferative protein of Tob/BTG family and typically involved in the tumorigenesis and T cell activation. Although TOB1 is associated with T helper 17 cell-related autoimmunity, its role in modulating T cell-mediated immune responses in IBD remains poorly understood. Here, we explored its expression and the underlying mechanisms involved in the pathogenesis of inflammatory bowel disease (IBD).
TOB1 and ID2 expression in IBD patients was examined by quantitative real time polymerase chain reaction and immunohistochemistry. IBD CD4 T cells were transfected with lentivirus expressing TOB1, ID2, TOB1 short hairpin RNA and ID2 short hairpin RNA, respectively, and Tob1CD4 T cells were transfected with lentivirus expressing Id2. Experimental colitis was established in Tob1 mice by trinitrobenzene sulfonic acid enema and in Rag1 mice reconstituted with Tob1CD45RBCD4 T cells to further explore the role of Tob1 in intestinal mucosal inflammation. Splenic CD4 T cells of Tob1 mice were sorted to determine transcriptome differences by RNA sequencing.
TOB1 expression was decreased in inflamed mucosa and peripheral blood CD4 T cells of IBD patients compared with healthy subjects. Overexpression of TOB1 downregulated IBD CD4 T cells to differentiate into Th1/Th17 cells compared with control subjects. Severe colitis was observed in Tob1 mice through trinitrobenzene sulfonic acid enema or in Rag1 mice reconstituted with Tob1CD45RBCD4 T cells, compared with control animals. RNA sequencing analysis revealed ID2 as functional target of TOB1 to inhibit IBD CD4 T cell differentiation into Th1/Th17 cells. Mechanistically, TOB1 was associated with Smad4/5 to induce ID2 expression and restrain Th1/Th17 cell differentiation.
TOB1 restrains intestinal mucosal inflammation through suppressing Th1/Th17 cell-mediated immune responses via the Smad4/5-ID2 pathway. It may serve as a novel therapeutic target for treatment of human IBD.
TOB1 是 Tob/BTG 家族的一种抗增殖蛋白，通常参与肿瘤发生和 T 细胞激活。尽管 TOB1 与辅助性 T 细胞 17 型（Th17 细胞）相关自身免疫有关，但它在调节 IBD 中 T 细胞介导的免疫反应中的作用仍知之甚少。本研究旨在探讨其在炎症性肠病（IBD）发病机制中的表达及相关机制。
采用实时定量聚合酶链反应和免疫组织化学法检测 IBD 患者 TOB1 和 ID2 的表达。分别用慢病毒转染 IBD CD4 T 细胞过表达 TOB1、ID2、TOB1 短发夹 RNA 和 ID2 短发夹 RNA，用慢病毒转染 Tob1 小鼠的 CD45RBCD4 T 细胞过表达 Id2，构建实验性结肠炎模型，进一步探讨 Tob1 在肠道黏膜炎症中的作用。从 Tob1 小鼠脾中分选 CD4 T 细胞，通过 RNA 测序确定转录组差异。
与健康对照者相比，IBD 患者炎症黏膜和外周血 CD4 T 细胞中 TOB1 的表达降低。与对照组相比，TOB1 的过表达可使 IBD CD4 T 细胞向 Th1/Th17 细胞分化的能力降低。与对照组相比，通过三硝基苯磺酸灌肠或用 Tob1CD45RBCD4 T 细胞重建 Rag1 小鼠，可观察到 Tob1 小鼠发生严重结肠炎。RNA 测序分析显示 ID2 是 TOB1 抑制 IBD CD4 T 细胞向 Th1/Th17 细胞分化的功能靶点。机制上，TOB1 通过与 Smad4/5 结合诱导 ID2 表达，从而抑制 Th1/Th17 细胞分化。
TOB1 通过 Smad4/5-ID2 通路抑制 Th1/Th17 细胞介导的免疫反应，抑制肠道黏膜炎症。它可能成为治疗人类 IBD 的一种新的治疗靶点。
