Th17 Pathway Plasticity in the Pathogenesis of Inflammatory Bowel Disease

 描述（由申请人提供）：炎症性肠病发病机制中的Th 17通路可塑性。Th 17亚群涉及许多免疫介导的疾病，包括IBD。尽管Th 17/IL-23轴在肠道炎症中的重要性已被公认，但关于Th 17谱系的稳定性和IFN-γ在结肠炎发病机制中的作用仍存在问题。在人类和小鼠结肠炎中，在发炎的肠组织中发现表达IL-17 A或IFN-γ或两者的T细胞。在已发表的研究中，我们使用新型细胞因子报告小鼠发现，Th 17细胞表现出晚期发育可塑性，在IL-23的影响下，Th 17细胞可以以依赖于转录因子的方式偏离为IFN-γ +细胞（“Th 1样”细胞）Stat 4和T-bet。我们的新的初步数据表明，缺乏Stat 4或T-bet的Th 17细胞在体外向IFN-γ +细胞的转化中受损，并且它们的大肠杆菌生成潜力显著降低。类似地，缺乏IFN-γ的Th 17细胞不诱导结肠炎。我们假设IL-17 A和IFN-γ产生细胞在IL-23的影响下由共同的Th 17前体产生，并且在IBD发病机制中具有不同的作用：IFN-γ + Th 1样细胞是疾病发展所需的，而仅表达IL-17 A的成熟Th 17细胞是保护性的。在这项提案中，我们将探索晚期Th 17分化的多样性如何影响IBD的发展，通过使用最近创建的IL-17 A报告小鼠来（i）研究Th 17衍生的IL-17 A+和IFN-γ +细胞对结肠炎发展的贡献，以及（ii）定义Th 17途径衍生的Th 1样细胞驱动肠道炎症的机制。

 DESCRIPTION (provided by applicant): Th17 Pathway Plasticity in the Pathogenesis of Inflammatory Bowel Disease. The Th17 subset has been implicated in a number of immune-mediated diseases, including IBD. Despite the acknowledged importance of the Th17/IL-23 axis in intestinal inflammation, questions remain regarding stability of the Th17 lineage and the role of IFN- in colitis pathogenesis. In human and mouse colitis, T cells that express either IL-17A or IFN-, or both are found in inflamed intestinal tissues. In published studies we have found using novel cytokine reporter mice that Th17 cells show late developmental plasticity, such that under the influence of IL-23, Th17 cells can deviate to IFN-+ cells (`Th1-like' cells) in a mannr that is dependent on the transcription factors Stat4 and T-bet. Our new preliminary data show that Th17 cells deficient in Stat4 or T-bet are impaired in their transition to IFN-+ cells in vvo, and their colitogenic potential is markedly reduced. Similarly, Th17 cells that are deficient in IFN- do not induce colitis. We hypothesize that IL-17A and IFN- producing cells arise from common Th17 precursors under the influence of IL-23 and have distinct roles in IBD pathogenesis: IFN-+ Th1-like cells are required for disease development whereas mature Th17 cells that express only IL-17A are protective. In this proposal we will explore how late diversity n Th17 differentiation impacts IBD development by using recently created IL-17A reporter mice to (i) study the contribution of Th17-derived IL-17A+ and IFN-+ cells to the development of colitis and (ii) define mechanisms by which Th1-like cells derived from the Th17 pathway drive intestinal inflammation.