Innate and Adaptive Immunity to Microbial Flagellins in IBD

项目1：IBD中对微生物鞭毛蛋白的先天性和适应性免疫。我们与丰富的 微生物群与我们相互作用，并有助于我们的健康。肠道中宿主-微生物印迹相互作用 是复杂的，当紊乱时，可能会导致慢性炎症性肠道疾病（IBD）。我们有 先前发现了一簇鞭毛蛋白，作为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应答，但也可诱导致病性T细胞 导致IBD的细胞反应。这些鞭毛蛋白提供了一种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-IgA途径 维持正常小鼠体内微生物群的稳态。项目1的总体假设是CD 4 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， 但是这些途径有限制，超过这些限制，肠道炎症 结果我们将使用CBirl鞭毛蛋白T细胞受体转基因小鼠和新型细胞因子报告小鼠来解决这些问题。 的目标。目的1将探讨IL-23是否调节肠Treg-IgA途径维持肠内Treg-IgA途径的表达。 与微生物群的平衡。我们将进一步检验IL-23缺乏增加Foxp 3表达的假设。 并降低肠道中CD 4 T细胞的ROR γ t表达，这些变化反映在肠道中， 固有层中存在的Thi细胞与Thi 7细胞的数量，以及稳态Foxp 3：RORYt 平衡可以通过中和IL-6来改变。目的2将检验粘膜Th 7细胞 通过IL-17和IL-22对微生物群的作用， Th 17途径在Treg-lgA缺陷的伊加缺陷小鼠中扩增， 通路目的3将确定肠道Thi 7对微生物群的反应的控制机制，重点是伊加缺陷小鼠。该目的将确定通过CD 4 T细胞损伤或外源性CBirl Thi 7效应记忆细胞的转移引起的伊加缺陷小鼠中肠内稳态的扰动是否导致结肠炎，以及这些扰动是否导致Foxp 3：RORYt平衡的转变。最后，该目的将测试将外源性Thi 7（产生IL-10或FoxpS-/-）过继转移至结肠炎B6.lgA-/-小鼠是否可以恢复粘膜Thi 7应答的调节和由Thi 7细胞因子调节的下游元件的调节，尽管有活动性粘膜炎症。这些研究将对CD 4 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。该项目将广泛互动，并与项目2、3和4高度互补。

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.