Regulation of Mucosal Th17 Cell Responses by Intestinal Bacteria

众所周知，肠道免疫系统的功能取决于精细的平衡 在效应物、致耐受性和调节机制之间。这种平衡不仅在 预防疾病，但也提供灵活性，从而指导适当的免疫 反应已知这种体内平衡的任何组分的失调都有助于 IBD。已知肠道寄生菌影响多种免疫机制， IBD的模型依赖于微生物群的存在。然而，组成的作用， 微生物群i还没有被调查，是否不同的分类群的肠道细菌激活 免疫系统的具体分支是未知的。 Th 17细胞是一种新发现的辅助性T细胞群， 在IBD背景下的促炎作用。在稳定状态下，Th 17细胞仅存在于 在小肠固有层中，它们与Foxp 3+以良好调节平衡共存 调节性T细胞（Treg）。肠道微生物群的不同成分在调节 这一余额目前尚不清楚。 我们已经发现，Th 17：Treg的比例取决于肠道的组成。 微生物群目前提案的重点将是进一步研究肠道细菌在 这个过程我们的主要假设是小肠的特定成分 可以鉴定微生物群特异性地诱导Th 17细胞，该细胞具有保护功能， 肠子为了验证这一假设，我们建议：1）鉴定特异性诱导 Th 17细胞分化; 2）检查它们在体内的作用机制和3）测试它们的 参与粘膜和全身免疫。我们将在1）中执行大部分实验 在K99阶段和2）和3）中的大部分实验中，在K99的独立阶段， 奖 从这些研究中收集的信息将为我们理解 肠道细菌对肠道免疫反应的调节。最终目标将是 为IBD治疗策略的合理设计提供知识， 肠道菌群的组成或功能。

It is well recognized that the function of the intestinal immune system depends on the fine balance between effector, tolerogenic, and regulatory mechanisms. This balance is important not only in preventing disease, but also in providing flexibility and thus instructing the appropriate immune response. Dysregulation in any components of this homeostasis has been known to contribute to IBD. Intestinal commensal bacteria are known to affect multiple immune mechanisms and mouse models of IBD depend on the presence of microbiota. However, the role of the composition of the microbiota ihas not been investigated and whether different taxons of commensal bacteria activate specific branches of the immune system is not known. Th17 cells are a newly discovered helper T cell population that has been proposed to play pro-inflammatory role in the context of IBD. At steady state Th17 cells are exclusively present in the small intestinal lamina propria where they co-exist in a well-regulated balance with Foxp3+ regulatory T cells (Treg). The role of different components of the intestinal microbiota in regulating this balance is currently unknown. We have discovered that the Th17:Treg ratio depends on the composition of the intestinal microbiota. The focus of the current proposal will be to further investigate the role of gut bacteria in this process. Our main hypothesis is that specific components of the commensal intestinal microbiota can be identified to specifically induce Th17 cells with protective function in the intestine. To test this hypothesis, we propose to 1) identify bacterial taxons that specifically induce Th17 cell differentiation; 2) examine the mechanisms of their action in vivo and 3) test their involvement in both mucosal and systemic immunity. We will perform most of the experiments in 1) during the K99 phase and the bulk of the experiments in 2) and 3) in the independent phase of the award. Information gathered from these studies will provide major advances in our understanding of the regulation of intestinal immune responses by commensal bacteria. The ultimate goal will be to provide knowledge for the rational design of therapeutic strategies for IBD, based on modulations of the composition or function of the intestinal microbiota.