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: 10396536
• 负责人: CHYI S HSIEH
• 金额: $ 55.27万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10396536
• 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 dysbiosis; gut microbiota; imaging approach; in vivo; 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T细胞对病原菌的反应对于保护免受病原体的侵害至关重要，但当 对非病原体，可能是不适当的反应驱动疾病，如炎症性肠病， 疾病（IBD）。相反，Foxp3+调节性T细胞（Treg）对唾液酸的应答增强了对唾液酸的耐受性。 预防免疫介导的病理，如IBD。肠道细菌相互作用的相对优先级和背景 与免疫系统之间的关系在我们的理解中仍然存在重大差距。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，提供了一种替代途径， 免疫系统遇到肠道常驻细菌。此外，我们观察到肠道常驻细菌类群 通常被认为是促进耐受性的，当通过结肠途径遇到时， 差距。另外，我们发现抗原特异性外周血淋巴细胞（pT淋巴细胞）在很大程度上识别粘膜上皮细胞。 相关（MA）小鼠螺杆菌属在体外和体内，并遇到螺杆菌属发生 它是连续的，并且独立于GAP。这些数据表明，被认为是致病菌的细菌可以被 在体内平衡过程中pT3的有效诱导剂，相反，认为是耐受诱导的分类群， 梭菌在稳定状态下基本上不被免疫系统遇到，而是通过免疫系统遇到。 结肠GAP导致效应T细胞应答。我们假设，在一次袭击中， 肠道细菌是免疫应答结果的重要决定因素， 在控制与肠道常驻细菌的相互作用和反应方面发挥重要作用， 结肠间隙。在这个建议中，我们将通过以下步骤来评估这一假设：1）定义细胞抗原 通过粘膜联合（MA）和GAP 2）递送，定义了参与的树突状细胞（DC）亚群， 获得和呈递粘膜相关的和GAP递送的粘膜抗原，和3）确定 幽门螺杆菌对粘膜免疫系统的影响和对GAP递送抗原的应答。研究 本提案中概述的方法将通过确定特定的细菌分类群是如何 免疫系统和随后的免疫反应。这些知识可以用来 引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

项目成果

Regulatory T Cells Developing Peri-Weaning Are Continually Required to Restrain Th2 Systemic Responses Later in Life.

• DOI: 10.3389/fimmu.2020.603059
• 发表时间: 2020
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Knoop KA;McDonald KG;Hsieh CS;Tarr PI;Newberry RD
• 通讯作者: Newberry RD

Airway Microbiota-Host Interactions Regulate Secretory Leukocyte Protease Inhibitor Levels and Influence Allergic Airway Inflammation.

• DOI: 10.1016/j.celrep.2020.108331
• 发表时间: 2020-11-03
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Jaeger N;McDonough RT;Rosen AL;Hernandez-Leyva A;Wilson NG;Lint MA;Russler-Germain EV;Chai JN;Bacharier LB;Hsieh CS;Kau AL
• 通讯作者: Kau AL

Gut Helicobacter presentation by multiple dendritic cell subsets enables context-specific regulatory T cell generation.

• DOI: 10.7554/elife.54792
• 发表时间: 2021-02-03
• 期刊: eLife
• 影响因子: 7.7
• 作者: Russler-Germain EV;Yi J;Young S;Nutsch K;Wong HS;Ai TL;Chai JN;Durai V;Kaplan DH;Germain RN;Murphy KM;Hsieh CS
• 通讯作者: Hsieh CS