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：
9093572
负责人：
Mark B Jones
金额：
$ 6.04万
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/9093572
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 microbiota 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（由适用提供）：哮喘和气道炎症性疾病已成为美国急诊就诊的主要原因，与西方生活方式不育的不育以及拟议缺乏早期微生物抗原暴露有关的四个十年趋势。胃肠道与细菌的脆弱甘氨酸（Glyag）多糖A（PSA）已被证明可以教育免疫系统以限制肠道中的炎症程度。重新暴露于抗原后的有效免疫反应通常是通过抗原经验的记忆T细胞介导的，而调节性T（TREG）细胞通常在抑制免疫反应中起关键作用，通常是通过免疫抑制性细胞因子（如IL-10）的分泌。我们的初步数据表明，肠道暴露于PSA会增加抗原经历的CD4+CD45RBLOTEM细胞，这些抗原能够在炎症刺激下扩增外周组织中的IL-10产生。其他数据表明，这些CD45RBLOTEM细胞在体外共培养时会协同诱导Treg诱导IL-10产生。我们假设共生菌群通过共生特异性CD45RBLOTEM细胞和组织居民Treg之间的T细胞合作与周围免疫调节有关。在此提案中，我们将（1）确定T细胞的新途径的介体 T细胞的配位能够减弱外围抗原特异性记忆反应的大小，（2）（2）建立这种途径的原则证明，以改善实验性气道注入。这项研究将为卫生假说提供一个新的机械框架，从而使肠道中的微生物群和T细胞室之间的通信将共生产物连接到非特异性外围免疫免疫，从而降低了对炎症的敏感性。解剖此过程将为炎症性疾病和自身免疫的治疗提供基础，并通过口服特定的细菌糖剂量提供，并可能为治疗这些疾病的治疗提供新的T细胞的治疗靶标。