Factors Controlling Effector T Cell Maintenance in the Pathogenesis of Colitis

描述(申请人提供)：炎症性肠病(IBD)是一种免疫失调的疾病。动物模型和人类基因数据支持在至少某些形式的IBD的发病机制中无限制的Th17反应发挥核心作用。我们建立的细胞因子报告小鼠导致发现Th17细胞在其分化后期程序是灵活的，以至于在Th17承诺后接收到的细胞因子信号影响成熟Th17细胞的稳定性和表型，从而影响它们引起结肠炎的能力。虽然已经知道IL-6在启动Th17谱系承诺中是不可或缺的，但它在Th17通路晚期的作用尚不清楚。我们最近发现IL-6在成熟的Th17细胞的维持和致病中发挥了意想不到的作用。与野生型Th17细胞不同，IL-6缺乏的Th17细胞无法维持致病表型，也不会引发结肠炎。尽管早期对Th17细胞的承诺是通过IL-6与膜结合的IL-6RA(mIL-6R)介导的，mIL-6R与gp130进行信号转导(经典的IL-6信号)，但发育中的Th17细胞迅速从其表面切割mIL-6R，不重新表达可检测到的mIL-6R。因此，IL-6似乎通过反式信号作用于成熟的Th17细胞，其中gp130是通过与IL-6的复合体中的sIL-6R结合而激活的。因此，我们的数据表明，成熟的Th17细胞必须既产生IL-6，又通过反式信号对IL-6做出反应，才能诱发结肠炎。这确定了一个自分泌/旁分泌环路，IL-6可能通过该环路作用于Th17细胞，促进结肠炎。在这里，我们将定义IL-6促进Th17晚期发育的机制，以及这如何影响IBD的启动和永久存在。我们假设，由成熟的Th17细胞亚群产生的IL-6有助于维持致病的Th17和介导结肠炎的Th1样细胞。此外，我们假设经典的IL-6信号对于Th17谱系的规范是必不可少的，反式IL-6信号对于维持成熟的Th17和从共同的Th17前体发展而来的Th1样效应器是必不可少的；在缺乏IL-6反式信号的情况下，致病效应器T细胞不能持续存在，结肠炎得到减轻。为了验证这一假说，我们建立了新的报告基因敲除和敲除模型，用来识别和跟踪IL-6产生细胞，并剖析IL-6在Th17途径中晚期作用的特定机制，以调节其发病潜力。这些转基因模型得到了我们通过合作获得的新的阻断抗体和重组蛋白的补充。我们预计，这些研究将阐明Th17途径导致慢性免疫介导性疾病的新特征，并将促进针对Th17介导性疾病的更合理疗法的设计。

DESCRIPTION (provided by applicant): Inflammatory bowel diseases (IBD) are diseases of immune dysregulation. Animal models and human genetic data support a central role for unrestrained Th17 responses in the pathogenesis of at least some forms of IBD. Cytokine reporter mice that we have generated led to the discovery that Th17 cells are flexible in their late program of differentiation, such that cytokine signals received after Th17 commitment impact the stability and phenotype of mature Th17 cells so as to influence their ability to cause colitis. While it has been known for some time that IL-6 is indispensable for initiation of Th17 lineage commitment, its function late in the Th17 pathway is ill-defined. We have recently identified an unanticipated role for IL-6 in the maintenance and pathogenicity of mature Th17 cells. Unlike wildtype Th17 cells, IL-6-deficient Th17 cells are unable to sustain a pathogenic phenotype and do not induce colitis. Although early commitment to the Th17 lineage is mediated via binding of IL-6 to membrane-bound IL-6Ra (mIL-6R), which associates with gp130 for signal transduction ("classical" IL-6 signaling), developing Th17 cells rapidly cleave mIL-6R from their surface and do not re-express detectable mIL-6R. Thus, IL-6 appears to act on mature Th17 cells via trans signaling, in which gp130 is activated by binding of shed, soluble IL-6R (sIL-6R) in complex with IL-6. Accordingly, our data suggest that mature Th17 cells must both produce IL-6 and respond to IL-6 via trans signaling to induce colitis. This identifies an autocrine/paracrine loop by which IL-6 might act on Th17 cells to promote colitis. Here, we will define mechanisms by which IL-6 contributes to late Th17 development and how this impacts IBD initiation and perpetuation. We hypothesize that IL-6 produced by a subset of mature Th17 cells contributes to the maintenance of pathogenic Th17 and Th1-like cells that mediate colitis. Further, we posit that whereas classical IL-6 signaling is essential for Th17 lineage specification, trans IL-6 signaling is essential for the maintenance of mature Th17 and Th1-like effectors that develop from a common Th17 precursor; in the absence of IL-6 trans signaling, pathogenic effector T cells are not sustained and colitis is attenuated. To test this hypothesis, we have generated novel reporter knock-in and knockout models with which to identify and track IL-6 producing cells and dissect specific mechanisms by which IL-6 acts late in the Th17 pathway to regulate its potential for pathogenesis. These transgenic models are complemented by new blocking antibodies and recombinant proteins that we have acquired through collaboration. We anticipate that these studies will elucidate new features of the Th17 pathway that contribute to chronic immune-mediated disease and will facilitate the design of more rational therapeutics that target Th17-mediated disease.