Mechanisms of Mucosal Th17 Cell Induction By Segmented Filamentous Bacteria

描述(由申请人提供)：在这项建议中，我们将研究单个共生细菌物种诱导肠道固有层中特定效应CD4T细胞亚群产生的机制。共生细菌代表着一种不同的微生物群落，永久存在于所有哺乳动物的肠道中。作为一个群落，共生体已知会影响宿主免疫的多个方面。在许多自身免疫疾病，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，单个微生物区系成员如何调节宿主免疫以提供保护或加剧疾病尚不清楚，这阻碍了对参与的分子机制的识别。我们鉴定了一种共生的节段性丝状细菌(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着重要的保护作用，同时也有助于易感宿主的自身免疫，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，并导致增强对肠道感染的粘膜保护和自身免疫加剧。目前，SFB是唯一已知的诱导Th17细胞的共生体。我们建议确定负责检测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，IDC的一个亚群CD103+CD11b+DC的遗传消融会导致Th17细胞减少。我们将研究CD103+CD11b+DC是否是SFB在肠道中介导的效应所必需的。我们还将检查是否直接采集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定植这些模型，并评估相应机制在SFB介导的Th17细胞诱导中的作用。了解共生体调节T细胞稳态的机制，特别是Th17细胞的诱导，将有助于开发出模拟或拮抗这种定向调节炎性T细胞反应的机制，从而在肠道感染的情况下增强粘膜保护，或者在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.