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

• 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
• 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

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 疾病（炎症性肠病）。相反，Foxp3+ 调节性 T 细胞 (Treg) 对共生体的反应会增强对共生体的耐受性 预防免疫介导的病理学，例如炎症性肠病 (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。我们观察到生态失调会导致 结肠杯状细胞相关抗原通道（GAP）的形成，提供了另一种途径 免疫系统遇到肠道常驻细菌。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 差距。或者，我们发现抗原特异性外周血 (pTreg) 在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 稳态过程中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 结肠间隙导致效应 T 细胞反应。我们假设相遇的地点和路线 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 结肠间隙。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以及对 GAP 递送抗原的反应。研究 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 免疫系统遇到的以及随后的免疫反应。这些知识可以利用 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。