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

基本信息

批准号：
9025779
负责人：
Ivaylo Ivanov Ivanov
金额：
$ 34.74万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
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/9025779
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 LoxP-flanked allele Lymphoid Cell Mammals Mediating Modeling Molecular Mus Pathogenesis Play Production Regulation 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 microbiota pathogen prevent public health relevance research study response therapy development villin

项目摘要

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）：在此提案中，我们将研究单个共生细菌物种诱导特定效应子CD4 T细胞子集中肠道层层中的特定效应子CD4 T细胞子集的机制。共生细菌代表了一个多样的微生物群落，该群落永久驻留在所有哺乳动物的肠道中。作为一个社区，众所周知，共生会影响宿主免疫的多个方面。在许多自身免疫性条件下，该社区组成的扰动是疾病发病机理的重要决定因素，例如炎症性肠病（IBD），糖尿病，关节炎。但是，单个微生物群如何调节宿主免疫以提供保护或加剧疾病，这尚不清楚，这阻碍了参与分子机制的识别。我们确定了一个共同的，分割的丝状细菌（SFB），可以特异性地诱导肠道中的Th17细胞。 Th17细胞是促炎性细胞，可针对细菌和真菌病原体发挥重要保护作用，同时在易感宿主中有助于自身免疫，包括IBD和结肠炎。我们表明，小鼠中SFB的存在特异性诱导了Th17细胞，并导致粘膜保护抗肠道感染和自身免疫性加剧。目前，SFB是唯一诱导Th17细胞的共生。我们建议鉴定负责检测SFB并呈现抗原以诱导Th17细胞的宿主细胞。我们将研究肠道树突状细胞（IDC）的作用，这与肠道Th17细胞诱导有关。我们发现，一个IDC子集的遗传消融CD103+ CD11b+ DCS导致Th17细胞的降低。我们将检查肠道中SFB介导的效应是否需要CD103+ CD11b+ DC。我们还将检查SFB抗原是否直接采样以诱导SFB特异性TH17细胞。我们将利用我们具有无SFB和TH17细胞的遗传模型的集合。这将使我们能够用SFB定居这些模型，并评估专门在SFB介导的TH17细胞诱导中的相应机制的作用。了解CONSENS调节T细胞稳态的机制，尤其是TH17细胞诱导将使疗法的发展以模拟或拮抗这种机制，以方向调节炎症性T细胞反应，以促进粘膜保护的促进性粘膜保护，或者在IBD的炎症情况下炎症的降低。