Factors Controlling Effector T Cell Maintenance in the Pathogenesis of Colitis

描述（由申请人提供）：炎症性肠病（IBD）是免疫失调的疾病。动物模型和人类遗传数据支持不受限制的Th17反应在至少某些形式的IBD发病机制中发挥核心作用。我们培育的细胞因子报告小鼠发现Th17细胞在后期的分化程序中是灵活的，因此Th17承诺后接受的细胞因子信号会影响成熟Th17细胞的稳定性和表型，从而影响其引起结肠炎的能力。虽然一段时间以来人们已经知道IL-6对于Th17谱系承诺的启动是不可或缺的，但其在Th17途径后期的功能尚不明确。我们最近发现了IL-6在成熟Th17细胞的维持和致病性中意想不到的作用。与野生型Th17细胞不同，缺乏il -6的Th17细胞不能维持致病性表型，也不会诱导结肠炎。尽管早期对Th17谱系的承诺是通过IL-6与膜结合的IL-6Ra （mIL-6R）的结合介导的，mIL-6R与gp130相关，用于信号转导（“经典”IL-6信号转导），但发育中的Th17细胞迅速从其表面切割mIL-6R，并且不重新表达可检测的mIL-6R。因此，IL-6似乎通过反式信号传导作用于成熟的Th17细胞，其中gp130通过与IL-6复合物结合的可溶性IL-6R （sIL-6R）被激活。因此，我们的数据表明成熟的Th17细胞必须同时产生IL-6并通过反式信号传导对IL-6作出反应才能诱导结肠炎。这确定了一个自分泌/旁分泌回路，IL-6可能通过该回路作用于Th17细胞以促进结肠炎。在这里，我们将定义IL-6促进Th17晚期发展的机制，以及它如何影响IBD的发生和延续。我们假设成熟Th17细胞亚群产生的IL-6有助于维持介导结肠炎的致病性Th17和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，而反式IL-6信号对于维持由共同Th17前体发展而来的成熟Th17和th1样效应体是必不可少的；在缺乏IL-6反式信号的情况下，致病性效应T细胞不能持续，结肠炎减轻。为了验证这一假设，我们建立了新的报告基因敲入和敲除模型，用于识别和跟踪产生IL-6的细胞，并解剖IL-6在Th17通路晚期发挥作用以调节其潜在发病机制的具体机制。我们通过合作获得的新的阻断抗体和重组蛋白补充了这些转基因模型。我们预计这些研究将阐明Th17通路的新特征，这些特征有助于慢性免疫介导疾病，并将促进设计针对Th17介导疾病的更合理的治疗方法。

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. PUBLIC HEALTH RELEVANCE: Factors Controlling Effector T Cell Maintenance in the Pathogenesis of Colitis. Inflammatory bowel diseases are diseases of immune dysregulation mediated by CD4 T cells that have poorly restrained reactivity to components of the enteric bacterial flora. This proposal will address mechanisms by which cytokines control the maintenance and pathogenic potential of effector CD4 T that contribute to IBD pathogenesis. We expect that results from these studies will provide a basis for new interventions to curb pathogenic immunity to the intestinal microbiota in the treatment of human IBD.