Regulation of Mucosal Th17 Cell Responses by Intestinal Bacteria

描述（由申请人提供）： 众所周知，肠道免疫系统的功能取决于效应机制、致耐受机制和调节机制之间的良好平衡。这种平衡不仅在预防疾病方面很重要，而且在提供灵活性，从而指导适当的免疫反应方面也很重要。已知这种体内平衡的任何组分的失调都有助于IBD。已知肠道细菌影响多种免疫机制，IBD的小鼠模型取决于微生物群的存在。然而，微生物群组成的作用尚未研究，并且不同分类群的肠道细菌是否激活免疫系统的特定分支尚不清楚。Th 17细胞是一种新发现的辅助性T细胞群，已被提出在IBD的背景下发挥促炎作用。在稳定状态下，Th 17细胞仅存在于小肠固有层中，在那里它们与Foxp 3+调节性T细胞（Treg）以良好调节的平衡共存。肠道微生物群的不同组分在调节这种平衡中的作用目前尚不清楚。我们发现Th 17：Treg比例取决于肠道微生物群的组成。目前提案的重点将是进一步研究肠道细菌在这一过程中的作用。我们的主要假设是，可以鉴定出肠道微生物群的特定组分，以特异性地诱导肠道中具有保护功能的Th 17细胞。为了验证这一假设，我们建议1）确定细菌分类群，特异性诱导Th 17细胞分化; 2）检查其在体内的作用机制和3）测试其参与粘膜和全身免疫。我们将在K99阶段执行1）中的大部分实验，并在奖励的独立阶段执行2）和3）中的大部分实验。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提供重大进展。最终目标将是基于肠道微生物群的组成或功能的调节，为IBD治疗策略的合理设计提供知识。 公共卫生相关性： 我们提出了一个有吸引力的想法，即在稳态和疾病期间肠道免疫反应的性质是由肠道微生物群的组成控制的。 细菌的Th 17或Treg细胞诱导分类群及其作用机制的鉴定将允许通过调节肠道细菌的组成或其功能来调节免疫应答，从而设计用于IBD或肠道感染的新型治疗策略。

DESCRIPTION (provided by applicant): 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 [sic] 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. PUBLIC HEALTH RELEVANCE: We propose the attractive idea that the nature of the immune responses in the gut during both steady state and disease is controlled by the composition of the intestinal microbiota. Identification of Th17 or Treg cell-inducing taxons of bacteria and their mechanism of action will allow for the design of novel therapeutic strategies for IBD or intestinal infections by modulating the immune response through regulating the composition of gut bacteria or their function.