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.

项目摘要 效应器T细胞对病原菌的反应是保护免受病原体侵袭的关键，但当 对于非病原体，可能是导致肠道炎症等疾病的不适当反应的基础 疾病(IBD)。相反，Foxp3+调节性T细胞(Treg)对共生体的反应加强了对 预防免疫介导的病理，如IBD。肠道细菌相互作用的相对优先顺序和背景 与免疫系统的关系在我们的理解上仍然存在很大差距。我们观察到，生物失调会导致 结肠杯细胞相关抗原通道(GAP)的形成，提供了另一种途径，通过这种途径 免疫系统会遇到肠道内的细菌。此外，我们观察到肠道内驻留的细菌分类群 通常被认为是促进耐受性的，当通过结肠遇到时可以诱导效应器反应 差距。或者，我们发现抗原特异性外周血细胞(PTregs)主要识别粘膜 相关(MA)小鼠幽门螺杆菌在体外和体内，并遇到幽门螺杆菌 连续的，独立于间隙的。这些数据表明，被认为是致病细菌的细菌可以 在动态平衡期间，pTregs的有效诱导者，相反，被认为是耐受性诱导的类群， 在稳定状态下，免疫系统基本上不会遇到梭状芽胞杆菌，但会通过 结肠间隙导致效应器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 在控制肠道内细菌的相互作用和反应方面发挥重要作用 结肠缝隙。在本提案中，我们将通过以下几个方面对这一假设进行评估：1)定义共生抗原 通过粘膜联合(MA)和间隙传递2)定义参与的树突状细胞(DC)亚群 黏膜相关抗原和GAP递送的共生抗原的获取和呈递以及3)定义 幽门螺杆菌对粘膜免疫系统的影响和对GAP递送抗原的反应。研究 这项提案中概述的将通过确定细菌分类群的具体程度来填补我们理解上的空白 所遇到的免疫系统和随后的免疫反应。这一知识可以被利用 指导肠道微生物区系和免疫系统的操作，以‘重置’慢性炎症反应 并回到动态平衡状态。