Factors Controlling Effector T Cell Maintenance in the Pathogenesis of Colitis

结肠炎发病机制中效应 T 细胞维持的控制因素

• 批准号: 8515403
• 负责人: Casey T Weaver
• 金额: $ 30.75万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8515403
• 关键词: Address; Animal Model; Antibodies; Antigens; Attenuated; Binding; Biology; Blocking Antibodies; CD4 Positive T Lymphocytes; Cell Maintenance; Cell Maturation; Cell physiology; Cells; Characteristics; Chimeric Proteins; Chronic; Cleaved cell; Colitis; Collaborations; Commit; Complement; Complex; Crohn' s disease; Cytokine Signaling; Data; Development; Disease; Disease model; Effector Cell; Enteral; Functional disorder; Generations; Human; Human Genetics; Immune; Immune System Diseases; Immunity; Impotence; Inflammatory; Inflammatory Bowel Diseases; Interleukin-1; Interleukin-17; Interleukin-6; Intervention; Intestines; Knock-in Mouse; Knock-out; Maintenance; Mediating; Membrane; Modeling; Mus; Pathogenesis; Pathogenicity; Pathway interactions; Phenotype; Play; Principal Investigator; Production; Reagent; Recombinant Proteins; Reporter; Role; Signal Transduction; Specific qualifier value; Staging; Surface; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Transgenic Model; Universities; Wales; autocrine; base; cytokine; design; flexibility; interleukin-23; novel; paracrine; programs; response; therapeutic target; transcription factor

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.

描述（由申请人提供）：炎症性肠病（IBD）是免疫失调疾病。动物模型和人类遗传数据支持无限制的Th 17应答在至少某些形式的IBD的发病机制中的核心作用。我们已经产生的细胞因子报告小鼠导致发现Th 17细胞在其晚期分化程序中是灵活的，使得在Th 17定型后接收的细胞因子信号影响成熟Th 17细胞的稳定性和表型，从而影响它们引起结肠炎的能力。虽然一段时间以来已经知道IL-6对于Th 17谱系定型的起始是必不可少的，但其在Th 17途径后期的功能不明确。我们最近发现了IL-6在成熟Th 17细胞的维持和致病性中的一个意想不到的作用。与野生型Th 17细胞不同，IL-6缺陷型Th 17细胞不能维持致病性表型并且不诱导结肠炎。虽然早期定型为Th 17谱系是通过IL-6与膜结合的IL-6 Ra（mIL-6 R）结合介导的，其与gp 130结合用于信号转导（“经典”IL-6信号传导），但发育中的Th 17细胞迅速从其表面切割mIL-6 R，并且不重新表达可检测的mIL-6 R。因此，IL-6似乎通过反式信号传导作用于成熟的Th 17细胞，其中gp 130通过与IL-6复合的脱落的可溶性IL-6 R（sIL-6 R）的结合而被激活。因此，我们的数据表明，成熟的Th 17细胞必须既产生IL-6，又通过反式信号传导对IL-6作出反应，以诱导结肠炎。这确定了IL-6可能作用于Th 17细胞以促进结肠炎的自分泌/旁分泌回路。在这里，我们将定义IL-6促进晚期Th 17发育的机制，以及这如何影响IBD的启动和延续。我们推测，IL-6产生的一个子集的成熟的Th 17细胞有助于维持致病性Th 17和Th 1样细胞介导结肠炎。此外，我们认为，而经典的IL-6信号是必不可少的Th 17谱系的规范，反式IL-6信号是必不可少的成熟的Th 17和Th 1样效应细胞的发展，从一个共同的Th 17前体的维护;在IL-6反式信号的情况下，致病性效应T细胞不持续和结肠炎是减弱。为了验证这一假设，我们已经产生了新的报告基因敲入和敲除模型，用于识别和跟踪IL-6产生细胞，并剖析IL-6在Th 17通路后期发挥作用以调节其发病潜力的特定机制。这些转基因模型由我们通过合作获得的新的阻断抗体和重组蛋白补充。我们预计这些研究将阐明Th 17通路的新特征，这些新特征有助于慢性免疫介导的疾病，并将有助于设计针对Th 17介导的疾病的更合理的治疗方法。