The Role of Route of Entry by Bacterial Antigens on Colonic T Cell Responses

细菌抗原进入途径对结肠 T 细胞反应的作用

基本信息

批准号：
9912712
负责人：
CHYI S HSIEH
金额：
$ 55.24万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-23 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9912712
关键词：
Antibiotics Antigen Presentation Antigens Automobile Driving B-Lymphocytes Bacteria Bacterial Antigens Biological Assay Cells Chronic Coculture Techniques Colon Data Dendritic Cells Development Disease Environment FOXP3 gene Flow Cytometry Goblet Cells Health Promotion Helicobacter Homeostasis Image Immune Immune response Immune system Immunity In Vitro Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Intestines Investigation Knowledge Literature Location Manuscripts Mediating Metagenomics Mucosal Immune System Mucous Membrane Mus Outcome Pathogenesis Pathology Peripheral Phenotype Play Population Process Regulatory T-Lymphocyte Role Route T cell response T-Cell Development T-Lymphocyte T-cell receptor repertoire Time Work antigen-specific T cells base commensal bacteria dysbiosis effector T cell genetic approach gut bacteria gut microbiota imaging approach in vivo inflammatory disease of the intestine microbial pathobiont pathogen pathogenic bacteria prevent response transcriptome sequencing

项目摘要

Project Summary Effector T cell responses to pathogenic bacteria are crucial for protection from pathogens, but when directed toward non-pathogens, may underlie inappropriate responses driving disorders such as inflammatory bowel disease (IBD). Conversely, Foxp3+ regulatory T cell (Treg) responses to commensals enforce tolerance to prevent immune-mediated pathology such as IBD. The relative priority and context of gut bacterial interaction with the immune system remain significant gaps in our understanding. We observed that dysbiosis induces the formation of colonic goblet cell associated antigen passages (GAPs), providing an alternative route by which the immune system encounters gut resident bacteria. Further, we observed that gut resident bacteria taxa generally considered as tolerance-promoting can induce effector responses when encountered via colonic GAPs. Alternatively, we have found that antigen-specific peripheral (pTregs) largely recognize mucosal associated (MA) murine Helicobacter spp in vitro and in vivo, and that encounter of Helicobacter spp occurs continuously and is independent of GAPs. These data indicate that bacteria believed to be pathobionts can be potent inducers of pTregs during homeostasis, and in contrast, taxa believed to be tolerance inducing, Clostridia, are largely not encountered by the immune system in the steady state, but are encountered via colonic GAPs resulting in effector T cell responses. We hypothesize that the location and route of encounter of gut bacteria are important determinants of the outcome of immune responses and that the MA bacteria can play an important role in controlling the interactions and responses to gut resident bacteria encountered via colonic GAPs. In this proposal we will evaluate this hypothesis by: 1) defining the commensal antigens delivered via mucosal association (MA) and GAPs 2) defining the dendritic cell (DC) subsets involved in acquisition and presentation of mucosal associated and GAP delivered commensal antigens and 3) defining the effects of Helicobacter on the mucosal immune system and responses to GAP delivered antigens. Studies outlined in this proposal will fill the gaps in our understanding by identifying how specific bacterial taxa are encountered by the immune system and the subsequent immune responses. This knowledge can be leveraged to guide manipulations of the gut microbiota and the immune system to ‘reset’ chronic inflammatory responses and return to homeostasis.

项目概要效应 T 细胞对病原菌的反应对于防御病原体至关重要，但当受到指导时针对非病原体，可能是导致炎症性肠病等疾病的不当反应的基础离线时，Foxp3+ 调节性 T 细胞 (Treg) 对共生体的反应增强了对疾病的耐受性。预防免疫介导的病理学，例如 IBD 肠道细菌相互作用的相对优先级和背景。我们对免疫系统的理解仍然存在重大差距，我们观察到菌群失调会导致免疫系统失调。结肠杯状细胞相关抗原通道（GAP）的形成，提供了另一种途径此外，我们观察到肠道驻留细菌分类群。通常被认为是促进耐受性，当通过结肠遇到时可以诱导效应反应或者，我们发现抗原特异性外周血 (pTreg) 很大程度上识别粘膜。相关（MA）鼠螺杆菌在体外和体内，并且发生螺杆菌的遭遇连续且独立于 GAP。这些数据表明被认为是致病生物的细菌可以是。体内平衡过程中pTregs的有效诱导剂，相反，类群被认为是耐受诱导的，梭状芽胞杆菌，在稳定状态下基本上不会被免疫系统遇到，但会通过我们捕获了导致效应 T 细胞反应的结肠间隙的位置和路径。肠道细菌是免疫反应结果的重要决定因素，MA 细菌可以在控制与肠道常驻细菌的相互作用和反应方面发挥着重要作用在本提案中，我们将通过以下方式评估这一假设：1）定义共生抗原。通过粘膜关联 (MA) 和 GAP 传递 2) 定义参与的树突状细胞 (DC) 亚群粘膜相关抗原和 GAP 传递的共生抗原的获取和呈递以及 3) 定义螺杆菌对粘膜免疫系统的影响和对 GAP 递送抗原的反应。该提案中概述的内容将通过确定特定细菌类群的性质来填补我们理解上的空白免疫系统遇到的情况以及随后的免疫反应可以利用这些知识。指导肠道微生物群和免疫系统的操作以“重置”慢性炎症反应并恢复体内平衡。