Connecting the microbiota to peripheral immune quiescence by T cell crosstalk

通过 T 细胞串扰将微生物群与外周免疫静止联系起来

基本信息

批准号：
8834392
负责人：
Mark B Jones
金额：
$ 5.66万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8834392
关键词：
Abscess Adhesions Adoptive Transfer Animals Antigens Asthma Autoimmunity Automobile Driving Bacteroides fragilis Biological Assay Blocking Antibodies CCR9 gene CD4 Positive T Lymphocytes Carbohydrates Cell Communication Cells Chromatography Chronic Coculture Techniques Communication Data Demyelinations Development Disease Emergency department visit Equilibrium Experimental Autoimmune Encephalomyelitis Experimental Models Exposure to Gnotobiotic Goals Health Histology Human Hygiene Hypersensitivity Immune Immune response Immune system Immunity Immunization Immunologics Immunosuppression Immunosuppressive Agents In Vitro Indigenous Infection Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Interleukin-10 Intestines Lead Life Style Link Longevity Lung Maintenance Measures Mediating Mediator of activation protein Memory Microbe Modeling Molecular Mus Operative Surgical Procedures Oral Pathway interactions Patients Peripheral Play Polysaccharides Population Predisposition Process Production Proteomics Publishing Regulatory T-Lymphocyte Research Research Proposals Respiratory physiology Role Severities Signal Transduction Sterility Stimulus System Systems Development T memory cell T-Lymphocyte Therapeutic Tissues adaptive immunity airway inflammation base capsule cell motility chemokine receptor clinical application cytokine drug candidate experience gastrointestinal immunoregulation in vivo microorganism antigen mouse model mucosal site new therapeutic target novel pre-clinical prevent public health relevance research study response terminally differentiated effector memory (TEM) T cells therapeutic target transcriptome sequencing trend

项目摘要

DESCRIPTION (provided by applicant): Asthma and airway inflammatory disease has become the leading cause for ER visits in the US, a four- decade trend linked to the increasing sterility of western lifestyles and a proposed lack of early microbial antigen exposure. Gastrointestinal contact with the Bacteroides fragilis glycoantigen (GlyAg) polysaccharide A (PSA) has been shown to educate the immune system to limit the degree of inflammation in the gut. Effective immune responses upon re-exposure to an antigen is typically mediated through antigen-experienced memory T cells, whereas regulatory T (Treg) cells are known to play key roles in suppressing immune responses, generally through the secretion of immunosuppressive cytokines like IL-10. Our preliminary data show that gut exposure to PSA increases a population of antigen experienced CD4+CD45RbloTEM cells which are capable of amplifying IL-10 production in peripheral tissues upon inflammatory stimulus. Additional data demonstrates that these CD45RbloTEM cells synergistically induce IL-10 production with Tregs when co-cultured in vitro. We hypothesize that commensal microflora are linked to peripheral immunomodulation through T-cell cooperation between commensal-specific CD45RbloTEM cells and tissue-resident Tregs. In this proposal, we will (1) identify the mediator(s) by which this novel pathway of T cell T cell cooperation is capable of dampening the magnitude of antigen-specific memory responses in the periphery, and (2) establish proof-of-principle pre-clinical applications of this pathway to ameliorate experimental airway inflammation. This study will provide a novel mechanistic framework for the hygiene hypothesis, whereby communication between the microbiota in the gut and the T cell compartment links commensal products to non-specific peripheral immune quiescence resulting in reduced susceptibility to inflammation. Dissecting this process will provide a basis for the treatment of inflammatory disease and autoimmunity with oral delivery of specific bacterial glycoantigens, and may provide new T cell directed therapeutic targets for the treatment of these diseases.

描述（由申请人提供）：哮喘和气道炎症已成为美国急诊室就诊的主要原因，这是一个四年来的趋势，与西方生活方式的日益不孕以及早期胃肠道微生物抗原接触的缺乏有关。脆弱拟杆菌糖抗原 (GlyAg) 多糖 A (PSA) 已被证明可以教育免疫系统以限制肠道炎症程度。再次暴露于抗原时的反应通常是通过经历过抗原的记忆 T 细胞介导的，而众所周知，调节性 T (Treg) 细胞通常通过分泌 IL-10 等免疫抑制细胞因子来抑制免疫反应。初步数据表明，肠道暴露于 PSA 会增加经历抗原的 CD4+CD45RbloTEM 细胞群，这些细胞能够在炎症刺激下放大外周组织中 IL-10 的产生。当在体外共培养时，CD45RbloTEM 细胞与 Tregs 协同诱导 IL-10 产生。在本提案中，我们将通过共生特异性 CD45RbloTEM 细胞和组织驻留 Tregs 之间的 T 细胞合作，发现共生微生物群与外周免疫调节相关。 (1) 确定 T 细胞这一新途径的介质 T 细胞合作能够抑制外周抗原特异性记忆反应的强度，并且 (2) 建立该途径的临床前应用原理验证，以改善实验性气道炎症。这项研究将提供一个新的机制框架。对于卫生假说，肠道微生物群和 T 细胞区室之间的通讯将共生产物与非特异性外周免疫静止联系起来，从而降低对炎症的易感性。为口服特定细菌糖抗原治疗炎症性疾病和自身免疫性疾病奠定了基础，并可能为这些疾病的治疗提供新的T细胞定向治疗靶点。