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: 8334504
• 负责人: Casey T Weaver
• 金额: $ 31.86万
• 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/8334504
• 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 发病机制中的核心作用。我们培育的细胞因子报告小鼠发现Th17细胞在其晚期分化程序中具有灵活性，因此Th17定型后接收到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。虽然人们早已知道 IL-6 对于 Th17 谱系定型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 IL-6 在成熟 Th17 细胞的维持和致病性中具有意想不到的作用。与野生型 Th17 细胞不同，IL-6 缺陷的 Th17 细胞无法维持致病表型，也不会诱发结肠炎。尽管对 Th17 谱系的早期定型是通过 IL-6 与膜结合 IL-6Ra (mIL-6R) 的结合介导的，mIL-6R 与 gp130 结合进行信号转导（“经典”IL-6 信号传导），但发育中的 Th17 细胞会快速裂解mIL-6R 从其表面分离，并且不重新表达可检测到的 mIL-6R。因此，IL-6 似乎通过反式信号传导作用于成熟 Th17 细胞，其中 gp130 通过与 IL-6 形成复合物的脱落的可溶性 IL-6R (sIL-6R) 结合而被激活。因此，我们的数据表明，成熟的 Th17 细胞必须既产生 IL-6，又通过反式信号传导对 IL-6 做出反应，从而诱导结肠炎。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 细胞以促进结肠炎。在这里，我们将定义 IL-6 促进 Th17 晚期发育的机制，以及它如何影响 IBD 的发生和持续。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 信号传导对于 Th17 谱系规范至关重要，而反式 IL-6 信号传导对于维持从常见 Th17 前体发育而来的成熟 Th17 和 Th1 样效应子至关重要。在缺乏 IL-6 反式信号传导的情况下，致病性效应 T 细胞无法持续存在，结肠炎也会减弱。为了检验这一假设，我们生成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 Th17 途径后期发挥作用以调节其发病机制潜力的具体机制。这些转基因模型得到了我们通过合作获得的新阻断抗体和重组蛋白的补充。我们预计这些研究将阐明 Th17 通路导致慢性免疫介导疾病的新特征，并将有助于设计针对 Th17 介导疾病的更合理的疗法。