Mechanisms of Mucosal Th17 Cell Induction By Segmented Filamentous Bacteria

描述（由申请人提供）：在本提案中，我们将研究单个共生细菌物种诱导肠固有层中特定效应CD4 T细胞亚群产生的机制。共生细菌代表了一种永久居住在所有哺乳动物肠道内的多种微生物群落。众所周知，作为一个群落，共生体影响宿主免疫的多个方面。在许多自身免疫性疾病（如炎症性肠病（IBD）、糖尿病、关节炎）中，该群落组成的扰动是疾病发病机制的重要决定因素。然而，个体微生物群成员如何调节宿主免疫以提供保护或加剧疾病尚不清楚，这阻碍了参与分子机制的确定。我们发现了一种共栖的分节丝状细菌（SFB），它可以特异性地诱导肠道中的Th17细胞。Th17细胞是促炎细胞，对细菌和真菌病原体起重要的保护作用，同时在易感宿主中促进自身免疫，包括IBD和结肠炎。我们发现SFB在小鼠体内的存在特异性地诱导Th17细胞，并导致粘膜对肠道感染的保护增强和自身免疫的加剧。目前，SFB是唯一已知的诱导Th17细胞的共体。我们建议鉴定负责检测SFB和呈递抗原的宿主细胞，以诱导Th17细胞。我们将研究肠道树突状细胞（iDCs）在肠道Th17细胞诱导中的作用。我们发现，一种iDC亚群（CD103+CD11b+ dc）的基因消融会导致Th17细胞的减少。我们将研究sfb介导的肠道效应是否需要CD103+CD11b+ dc。我们还将检查是否直接取样SFB抗原来诱导SFB特异性Th17细胞。我们将利用我们重新衍生的无sfb和无Th17细胞的遗传模型的集合。这将使我们能够用SFB定殖这些模型，并评估相应机制在SFB介导的Th17细胞诱导中的作用。了解共体调节T细胞稳态的机制，特别是Th17细胞诱导，将有助于开发模拟或拮抗这种机制的治疗方法，以定向调节炎症T细胞反应，从而在肠道感染的情况下增强粘膜保护，或在IBD的情况下减少炎症。

DESCRIPTION (provided by applicant): In this proposal we will investigate the mechanisms by which an individual commensal bacterial species induces generation of a specific effector CD4 T cell subset in the intestinal lamina propria. Commensal bacteria represent a diverse microbial community that permanently resides in the intestines of all mammals. As a community, commensals are known to affect multiple aspects of host immunity. Perturbations in the composition of this community are important determinants of disease pathogenesis in many autoimmune conditions, e.g. inflammatory bowel diseases (IBD), diabetes, arthritis. However, how individual microbiota members modulate host immunity in order to provide protection or exacerbate disease is unclear, which has impeded identification of participating molecular mechanisms. We identified a commensal, segmented filamentous bacteria (SFB), that can specifically induce Th17 cells in the gut. Th17 cells are pro-inflammatory cells that play important protective roles against bacterial and fungal pathogens while at the same time contribute to autoimmunity, including IBD and colitis, in susceptible hosts. We showed that presence of SFB in mice specifically induces Th17 cells and leads to increase in mucosal protection against intestinal infections and exacerbation of autoimmunity. Presently, SFB are the only known commensal that induces Th17 cells. We propose to identify host cells responsible for detecting SFB and presenting antigens in order to induce Th17 cells. We will examine the role of intestinal dendritic cells (iDCs), which have been implicated in gut Th17 cell induction. We have discovered that genetic ablation of one iDC subset, the CD103+CD11b+ DCs, leads to a decrease in Th17 cells. We will examine whether CD103+CD11b+ DCs are required for SFB-mediated effects in the gut. We will also examine if SFB antigens are directly sampled to induce SFB-specific Th17 cells. We will utilize a collection of genetic models that we have re- derived SFB-free and Th17 cell-free. This will allow us to colonize these models with SFB and assess the role of the corresponding mechanisms specifically in SFB-mediated Th17 cell induction. Understanding the mechanisms by which commensals modulate T cell homeostasis, and in particular Th17 cell induction will allow for the development of therapies to mimic or antagonize such mechanisms for the directional regulation of inflammatory T cell responses for the boost of mucosal protection in the case of intestinal infections or the decrease in inflammation in the case of IBD.