Th17 Pathway Plasticity in the Pathogenesis of Inflammatory Bowel Disease

 描述(申请人提供)：炎症性肠病发病机制中的通路可塑性。Th17亚群与包括IBD在内的许多免疫介导性疾病有关。尽管公认Th17/IL-23轴在肠道炎症中的重要性，但关于Th17谱系的稳定性和干扰素-在结肠炎发病机制中的作用仍存在疑问。在人类和小鼠结肠炎中，在炎症的肠道组织中可以发现表达IL-17A或干扰素-或两者都表达的T细胞。在已发表的研究中，我们利用新的细胞因子报告鼠发现，Th17细胞显示出发育后期的可塑性，因此在IL-23的影响下，Th17细胞可以偏离干扰素-+细胞(Th1样细胞)，这一过程依赖于转录因子STAT4和T-bet。我们的新的初步数据显示，缺乏STAT4或T-bet的Th17细胞在体内向干扰素-+细胞转化的过程中受到损害，其结肠性潜能显著降低。同样，缺乏干扰素-的Th17细胞不会引发结肠炎。我们假设IL-17A和干扰素-产生的细胞来自IL-23影响下的普通Th17前体细胞，并且在IBD的发病机制中具有不同的作用：干扰素-+Th1样细胞是疾病发展所必需的，而成熟的只表达IL-17A的Th17细胞是保护性的。在这项建议中，我们将通过使用最近创建的IL-17A报告小鼠来探索Th17细胞分化的晚期多样性如何影响IBD的发展，以(I)研究Th17来源的IL-17A+和干扰素-+细胞在结肠炎发展中的作用，以及(Ii)确定从Th17途径衍生的Th1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.