Innate and Adaptive Immunity to Microbial Flagellins in IBD

IBD 中微生物鞭毛蛋白的先天性和适应性免疫

• 批准号: 7992801
• 负责人: CHARLES O ELSON
• 金额: $ 95.52万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7992801
• 关键词: Address; Adoptive Transfer; Affect; American; Antigens; B-Lymphocytes; Bacteria; CD4 Positive T Lymphocytes; Cell Maintenance; Cells; Chronic; Colitis; Complex; Development; Disease; Effector Cell; Elements; Epithelial; Epithelial Cells; Epithelium; Equilibrium; Flagellin; Frequencies; Gene Targeting; Genes; Health; Homeostasis; IL10 gene; Immune response; Immunodominant Antigens; Immunoglobulin A; Impairment; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Interleukin-10; Interleukin-17; Interleukin-6; Intestines; Lamina Propria; Memory; Mucins; Mucosal Immune Responses; Mucositis; Mus; Pathway interactions; Play; Production; Regulation; Regulatory T-Lymphocyte; Reporter; Role; Signal Transduction; T cell response; T-Cell Receptor; T-Lymphocyte; TGFB1 gene; Testing; Transgenic Mice; Transgenic Organisms; Up-Regulation; adaptive immunity; chemokine; cytokine; imprint; interleukin-22; interleukin-23; microbial; novel; response

Project 1: Innate and Adaptive Immunity to Microbial Flagellins in IBD. We co-exist with an abundant microbiota that interacts with us and contributes to our health. Host-microblota interactions in the intestine are complex, and when disordered, can result in chronic inflammatory bowel disease (IBD). We have previously discovered a cluster of flagellins that serve as immunodominant antigens of the microbiota. These flagellins stimulate mucosal immune responses in normal hosts, but can also induce pathogenic T cells responses resulting in IBD. These flagellins provide a probe of both the normal mucosal immune response, as well as the abnormal response occurring in IBD. In the previous cycle we have generated a CBirl flagellin T cell receptor transgenic mouse, which was used to discover a T regulatory-lgA pathway maintaining homeostasis with the microbiota in normal mice. The overall hypothesis of Project 1 is that CD4 T cell effector subsets in the intestine maintain homeostasis by a number of different pathways that can compensate for one another, but that these pathways have limits beyond which intestinal inflammation results. We will use CBirl flagellin T cell receptor transgenic and novel cytokine reporter mice to address the following aims. Aim 1 will ask whether IL-23 regulates the intestinal Treg-lgA pathway maintaining homeostasis with the microbiota. We will further test the hypothesis that IL-23 deficiency increases Foxp3 and decreases RORyt expression by CD4 T cells in the intestine, that these changes are reflected in the numbers of Tregs vs. Thi 7 cells present in the lamina propria, and that the homeostatic Foxp3:RORYt balance can be altered by neutralization of IL-6. Aim 2 will test the hypothesis that mucosal Thi7 cells constitute a second pathway of homeostasis with the microbiota via IL-17 and IL-22 effects on the epithelium, and that this Th17 pathway is expanded in IgA deficient mice that are deficient in the Treg-lgA pathway. Aim 3 will determine the mechanisms of control of the intestinal Thi7 response to the microbiota focusing on IgA deficient mice. This Aim will determine whether perturbation of intestinal homeostasis in IgA deficient mice by impairment of CD4 Tregs or transfer of exogenous CBirl Thi 7 effector memory cells, results in colitis and whether these perturbations result in a shift in the Foxp3:RORYt balance. Lastly, this Aim will test whether adoptive transfer of exogenous Tregs, either IL-10-producing or FoxpS"", to colitic B6.lgA-/- mice can restore regulation of mucosal Thi 7 responses and of the downstream elements regulated by Thi7 cytokines, despite active mucosal inflammation. These studies will provide important new understanding about mechanisms of CD4 T cell maintenance of homeostasis, as well as the limits of these homeostatic pathways. This project will interact extensively and is highly complementary to Projects 2, 3, and 4.

项目 1：IBD 中微生物鞭毛蛋白的先天和适应性免疫。我们与丰富的资源共存 与我们相互作用并有助于我们健康的微生物群。肠道中宿主与微生物的相互作用 它们很复杂，如果出现紊乱，可能会导致慢性炎症性肠病 (IBD)。我们有 之前发现了一簇鞭毛蛋白，它们充当微生物群的免疫显性抗原。 这些鞭毛蛋白刺激正常宿主的粘膜免疫反应，但也可以诱导致病性 T 细胞反应导致 IBD。这些鞭毛蛋白提供了正常粘膜免疫的探针 反应，以及 IBD 中发生的异常反应。在上一个周期中我们生成了一个 CBirl 鞭毛蛋白 T 细胞受体转基因小鼠，用于发现 T 调节性 IgA 通路 维持正常小鼠微生物群的稳态。项目1的总体假设是CD4 肠道中的 T 细胞效应子亚群通过许多不同的途径维持体内平衡，这些途径可以 相互补偿，但这些途径都有其局限性，超出了肠道炎症的范围 结果。我们将使用CBirl鞭毛蛋白T细胞受体转基因和新型细胞因子报告小鼠来解决 以下目标。目标 1 将询问 IL-23 是否调节肠道 Treg-IgA 通路维持 与微生物群的稳态。我们将进一步检验 IL-23 缺乏会增加 Foxp3 的假设 并降低肠道中 CD4 T 细胞的 RORyt 表达，这些变化反映在 固有层中存在的 Tregs 与 Thi 7 细胞的数量，以及稳态 Foxp3:RORYt IL-6 的中和可改变平衡。目标 2 将检验粘膜 Thi7 细胞的假设 通过 IL-17 和 IL-22 对微生物群的影响构成了微生物群稳态的第二条途径 上皮细胞，并且该 Th17 通路在缺乏 Treg-IgA 的 IgA 缺陷小鼠中得到扩展 途径。目标 3 将确定肠道 Thi7 对微生物群反应的控制机制，重点关注 IgA 缺陷小鼠。该目标将确定 IgA 缺陷小鼠肠道稳态是否因 CD4 Tregs 损伤或外源 CBirl Thi 7 效应记忆细胞转移而扰乱，导致结肠炎，以及这些扰动是否导致 Foxp3:RORYt 平衡的变化。最后，该目标将测试将外源性 Tregs（产生 IL-10 的或 FoxpS""）过继转移至结肠炎 B6.lgA-/- 小鼠是否可以恢复粘膜 Thi 7 反应的调节以及受 Thi7 细胞因子调节的下游元件的调节，尽管粘膜炎症活跃。这些研究将为 CD4 T 细胞维持稳态的机制以及这些稳态途径的局限性提供重要的新认识。该项目互动广泛，与项目2、3、4具有很强的互补性。