Mechanisms of Mucosal Th17 Cell Induction By Segmented Filamentous Bacteria

分节丝状细菌诱导粘膜 Th17 细胞的机制

• 批准号: 8650824
• 负责人: Ivaylo Ivanov Ivanov
• 金额: $ 34.63万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8650824
• 关键词: Ablation; Adverse effects; Affect; Antigen Presentation; Antigen-Presenting Cells; Antigens; Arthritis; Autoimmune Process; Autoimmunity; Bacteria; CD27 Antigens; CD4 Positive T Lymphocytes; Cell Count; Cell Differentiation process; Cell Lineage; Cells; Chronic; Colitis; Collection; Communities; Dendritic Cells; Diabetes Mellitus; Diphtheria Toxin; Disease; Effector Cell; Environment; Epithelial Cells; Generations; Genetic; Genetic Models; Homeostasis; Hybridomas; ITGAM gene; ITGAX gene; Immune; Immune response; Immunity; In Vitro; Incubated; Individual; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Interleukin-17; Interleukin-2; Interleukin-6; Intestines; Laboratories; Lamina Propria; Lead; Lymphoid Cell; Mammals; Mediating; Modeling; Molecular; Mus; Pathogenesis; Play; Production; Regulation; Relative (related person); Reporter; Reporting; Research Design; Role; Sampling; Specificity; Staining method; Stains; System; T cell response; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Transgenic Mice; Transgenic Organisms; Work; cell type; commensal microbes; cytokine; in vivo; interleukin-22; interleukin-23; member; microbial community; pathogen; prevent; public health relevance; research study; response; therapy development; villin

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.

描述（由申请人提供）：在本提案中，我们将研究单个肠道细菌物种诱导肠固有层中特异性效应CD4 T细胞亚群产生的机制。共生细菌代表了永久存在于所有哺乳动物肠道中的多样化微生物群落。作为一个社区，已知寄生虫影响宿主免疫的多个方面。在许多自身免疫性疾病中，该群落组成的扰动是疾病发病机制的重要决定因素，例如炎症性肠病（IBD）、糖尿病、关节炎。然而，个体微生物群成员如何调节宿主免疫力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鉴定。 我们鉴定了一种可特异性诱导肠道中Th17细胞的杆状、分节丝状细菌（SFB）。Th17细胞是促炎细胞，其在抵抗细菌和真菌病原体方面发挥重要的保护作用，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在小鼠中的存在下特异性诱导Th17细胞，并导致增加对肠道感染和自身免疫恶化的粘膜保护。目前，SFB是唯一已知的诱导Th17细胞的药物。 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）的作用，这与肠道Th17细胞诱导有关。我们已经发现，一种iDC亚群（CD103+CD11b+ DC）的基因消融导致Th17细胞的减少。我们将研究是否需要CD103+CD11b+ DCs的SFB介导的影响在肠道。我们还将检查是否直接采样SFB抗原以诱导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。了解免疫调节T细胞稳态的机制，特别是Th17细胞诱导，将允许开发模拟或拮抗这种机制的疗法，用于定向调节炎性T细胞应答，以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。