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微妙的平衡。 在效应器、耐受性和调节机制之间。这种平衡很重要，不仅是在 预防疾病，还在提供灵活性，从而指导适当的免疫 回应。已知，这种动态平衡的任何组成部分的失调都有助于 IBD。已知肠道共生菌影响多种免疫机制和小鼠 IBD的模型依赖于微生物区系的存在。然而，组成的作用 微生物区系I尚未被调查，以及不同的共生菌分类群是否激活 免疫系统的特定分支尚不清楚。 Th17细胞是一种新发现的辅助性T细胞群，已被提出发挥作用 炎症性肠病的促炎作用。在稳定状态下，Th17细胞仅存在于 它们与Foxp3+共存的小肠固有层与Foxp3+处于良好调节的平衡状态 调节性T细胞(Treg)。肠道微生物区系的不同成分在调节中的作用 这一余额目前尚不清楚。 我们发现Th17：Treg的比例取决于肠道的组成 微生物区系。目前提案的重点将是进一步研究肠道细菌在 这一过程。我们的主要假设是共生肠道的特定成分 可以确定微生物群可以特异性地诱导具有保护功能的Th17细胞。 肠子。为了验证这一假设，我们建议1)鉴定能够特异性地诱导 Th17细胞分化；2)检测其在体内的作用机制；3)检测其 参与粘膜免疫和系统免疫。我们将在1)中执行大部分实验 在K99阶段和2)和3)中的大部分实验期间， 获奖。 从这些研究中收集的信息将为我们理解 肠道共生菌对肠道免疫反应的调节。最终目标将是 为基于调节的IBD治疗策略的合理设计提供知识 肠道微生物区系的组成或功能。

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.