Th17 Pathway Plasticity in the Pathogenesis of Inflammatory Bowel Disease

炎症性肠病发病机制中的 Th17 通路可塑性

基本信息

批准号：
9099835
负责人：
Casey T Weaver
金额：
$ 33.08万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9099835
关键词：
Ablation Address CD4 Positive T Lymphocytes Cells Colitis Crohn&apos s disease Data Development Disease Disease model Equilibrium Gene Expression Health Human Human Genetics Immune Immune System Diseases Immune system Immunity Immunodeficient Mouse Inflammatory Inflammatory Bowel Diseases Inflammatory disease of the intestine Interferon Gamma Receptor Complex Interferon Type II Interferons Interleukin-1 Interleukin-17 Interleukin-6 Intervention Intestines Knock-in Knockout Mice Life Maintenance Mediating Modeling Mus Pathogenesis Pathogenicity Pathway interactions Play Population Production Publishing Receptor Signaling Reporter Repression Role STAT4 gene STAT4 protein Signal Transduction Specific qualifier value T-Lymphocyte T-Lymphocyte Subsets Testing Th1 Cells Tissues Transforming Growth Factor beta base cellular targeting chemokine cytokine developmental plasticity gut microbiota interleukin-22 interleukin-23 microbiota novel programs response transcription factor

项目摘要

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.

描述（由申请人提供）：炎症性肠病发病机制中的 Th17 通路可塑性尽管 Th17/IL-23 轴在肠道中的重要性已得到公认，但 Th17 亚群与许多免疫介导的疾病有关。炎症，关于 Th17 谱系的稳定性和 IFN-γ 在结肠炎发病机制中的作用仍然存在疑问。在人类和小鼠结肠炎中，表达任一的 T 细胞。在发炎的肠道组织中发现了 IL-17A 或 IFN- 或两者，在已发表的研究中，我们使用新型细胞因子报告小鼠发现 Th17 细胞表现出晚期发育可塑性，因此在 IL-23 的影响下，Th17 细胞可能会发生偏差。 IFN-γ+ 细胞（“Th1 样”细胞）的作用依赖于转录因子 Stat4 和 T-bet 我们新的初步数据表明，Th17 细胞缺乏 Stat4 或 T-bet。 T-bet 在体内向 IFN-γ+ 细胞的转变受到损害，并且其致结肠炎的潜力显着降低，同样，缺乏 IFN-γ 的 Th17 细胞不会诱发结肠炎。  产生细胞在 IL-23 的影响下由常见的 Th17 前体产生，在 IBD 发病机制中具有独特的作用： IFN-+ Th1 样细胞是疾病发展所必需的，而成熟的 Th1 样细胞是疾病发展所必需的仅表达 IL-17A 的 Th17 细胞具有保护性。在本提案中，我们将通过使用最近创建的 IL-17A 报告小鼠来探索 Th17 分化的晚期多样性如何影响 IBD 的发展，以 (i) 研究 Th17 衍生的 IL-17A+ 和IFN-γ+ 细胞与结肠炎的发展有关，并且 (ii) 定义了源自 Th17 途径的 Th1 样细胞驱动肠道炎症的机制。