The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn's disease.
The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn's disease.
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DOI：
10.1084/jem.20011956
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发表时间：
2002-05-06
期刊：
影响因子：
--
通讯作者：
Blumberg RS
中科院分区：
文献类型：
--
作者：
Neurath MF;Weigmann B;Finotto S;Glickman J;Nieuwenhuis E;Iijima H;Mizoguchi A;Mizoguchi E;Mudter J;Galle PR;Bhan A;Autschbach F;Sullivan BM;Szabo SJ;Glimcher LH;Blumberg RS
由T细胞分泌的前和后细胞因子之间的平衡调节炎症性肠病（IBD）的起始和持续。特别地，干扰素（IFN）-γ/白细胞介素（IL）-4和转化生长因子（TGF）-β活性之间的平衡控制慢性肠道炎症。然而，引起这些反应的分子途径并不清楚。在这里，我们描述了转录因子T-bet在控制粘膜细胞因子平衡和临床疾病中的关键作用。我们研究了T-bet的表达和功能的IBD患者和粘膜T细胞在各种辅助性T细胞（Th）1-和Th 2-介导的慢性肠道炎症的动物模型，利用小鼠缺乏T-bet和逆转录病毒转导技术，分别。尽管逆转录病毒转导CD 62 L + CD 4 + T细胞中的T-bet加重了重建的SCID小鼠中的结肠炎，但T-bet缺陷的T细胞在过继转移实验中未能诱导结肠炎，这表明T-bet的过表达对于促进体内Th 1介导的结肠炎是必要的且足够的。此外，T-bet缺陷型CD 62 L − CD 4 + T细胞在Th 1介导的结肠炎中表现出增强的保护功能，并表现出增加的TGF-β信号传导，这表明T-bet驱动的T细胞活化途径控制IFN-γ/IL-4和TGF-β反应之间的肠道平衡以及T细胞介导的结肠炎中慢性肠道炎症的发展。此外，发现TGF-β抑制T-bet表达，表明粘膜T细胞中TGF-β和T-bet之间的相互关系。总之，我们的数据表明T-bet在T细胞介导的结肠炎的发病机制中起关键调节作用。特异性靶向该通路可能是治疗克罗恩病和其他由Th 1 T淋巴细胞介导的自身免疫性疾病的一种有前途的新方法。
The balance between pro and antiinflammatory cytokines secreted by T cells regulates both the initiation and perpetuation of inflammatory bowel diseases (IBD). In particular, the balance between interferon (IFN)-γ/interleukin (IL)-4 and transforming growth factor (TGF)-β activity controls chronic intestinal inflammation. However, the molecular pathways that evoke these responses are not well understood. Here, we describe a critical role for the transcription factor T-bet in controlling the mucosal cytokine balance and clinical disease. We studied the expression and function of T-bet in patients with IBD and in mucosal T cells in various T helper (Th)1- and Th2-mediated animal models of chronic intestinal inflammation by taking advantage of mice that lack T-bet and retroviral transduction techniques, respectively. Whereas retroviral transduction of T-bet in CD62L+ CD4+ T cells exacerbated colitis in reconstituted SCID mice, T-bet–deficient T cells failed to induce colitis in adoptive transfer experiments suggesting that overexpression of T-bet is essential and sufficient to promote Th1-mediated colitis in vivo. Furthermore, T-bet–deficient CD62L− CD4+ T cells showed enhanced protective functions in Th1-mediated colitis and exhibited increased TGF-β signaling suggesting that a T-bet driven pathway of T cell activation controls the intestinal balance between IFN-γ/IL-4 and TGF-β responses and the development of chronic intestinal inflammation in T cell–mediated colitis. Furthermore, TGF-β was found to suppress T-bet expression suggesting a reciprocal relationship between TGF-β and T-bet in mucosal T cells. In summary, our data suggest a key regulatory role of T-bet in the pathogenesis of T cell–mediated colitis. Specific targeting of this pathway may be a promising novel approach for the treatment of patients with Crohn's disease and other autoimmune diseases mediated by Th1 T lymphocytes.
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