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：对IBD中微生物鞭毛蛋白的先天和适应性免疫。我们与丰富的共存 与我们互动并有助于我们的健康的微生物群。肠道中的宿主膜细胞界相互作用 很复杂，并且在无序时会导致慢性炎症性肠病（IBD）。我们有 以前发现了一群鞭毛素，它们是微生物群的免疫主导抗原。 这些鞭毛蛋白刺激正常宿主中的粘膜免疫反应，但也可以诱导致病性T 细胞响应导致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 CBIRL鞭毛蛋白T细胞受体转基因小鼠，用于发现T调节途径 在正常小鼠中维持与微生物群的体内平衡。项目1的总体假设是CD4 肠道中的T细胞效应子亚群维持稳态的多种不同的途径 互相补偿，但是这些途径有限制，超出了肠道炎症 结果。我们将使用CBIRL Flagellin T细胞受体转基因和新型的细胞因子报告基因小鼠来解决 以下目标。 AIM 1将询问IL-23是否调节维护肠道Treg-LGA途径 稳态与微生物群。我们将进一步检验以下假设：IL-23缺乏症增加FOXP3 并降低了肠中CD4 T细胞的Roryt表达，这些变化反映在 lamina lamina Propria中存在的Tregs数量与Thi 7个单元 平衡可以通过中和IL-6改变。 AIM 2将检验粘膜Thi7细胞的假设 通过IL-17和IL-22对微生物群的第二途径构成对稳态的第二个途径 上皮，并且该Th17途径在IgA缺乏的小鼠中扩展 路径。 AIM 3将确定肠Thi7对菌群的控制的机制，该反应集中在IgA缺乏小鼠上。这个目标将确定通过损害CD4 Tregs或外源性CBIRL THI 7效应记忆细胞的转移，导致结肠炎以及这些扰动是否会导致FOXP3：Roryt Blaces的转变，这将确定IgA缺乏小鼠肠稳态的扰动。最后，此目标将测试外源性Treg的收养转移，即产生IL-10或FOXPS“”，“”到Colitic B6.lga - / - 小鼠是否可以恢复粘膜的调节，以及由Thi7细胞因子调节的下游元件的调节，尽管有活跃的粘膜炎症。这些研究将为CD4 T细胞维持稳态的机制以及这些体内稳态途径的局限性提供重要的新理解。该项目将广泛互动，并与项目2、3和4高度互补。