The Role of CXCR6 in Lung Airway Memory T cell Recruitment and Maintenance

CXCR6 在肺气道记忆 T 细胞招募和维持中的作用

基本信息

  • 批准号:
    8649841
  • 负责人:
  • 金额:
    $ 4.77万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-09-05 至 2017-11-04
  • 项目状态:
    已结题

项目摘要

Project Summary Very fragile yet highly structured, the lung is assaulted with potential pathogens, allergens, and irritants with every breath. Yearly epidemics of influenza virus are a significant source of morbidity and mortality, presenting a major health obstacle with high economic burden for the United States and the world. Notably, the short incubation period, high infection rate, and rapid transmission of the influenza virus uniquely complicates the care of patients with pulmonary co-morbidities. However, the presence of effector memory CD8 T cells in the lungs can quickly control the local spread of a pathogen while mitigating an undesired and potentially deleterious wide-spread inflammatory response in the lungs. Key findings from human and animal model studies denoted that the protective efficacy of airway-resident memory CD8 T (TARM) cells directly correlates with the number of memory CD8 T cells present in the lung airways at the time of influenza challenge; as the number of TARM cells declined, so did protection from influenza challenge. Yet, it is unknown how TARM cells are maintained at the site of infection, the lung airways, where they are uniquely positioned to rapidly respond to an influenza infection. The first step in the process is elucidating the manner by which these memory CD8 T cells enter the lung from the general circulation. It is accepted that a chemokine receptor and adhesion molecule pair is necessary for trafficking of resident memory CD8 T (TRM) cell subsets to specific peripheral tissues. While the adhesion molecule has been identified, the chemokine receptor necessary for steady-state recruitment of memory CD8 T cells to the lungs has not. Identification of this specific chemokine receptor and elucidation of the mechanisms that regulate its expression are the basis of this proposal. The goal of the proposed project is to define the role of the chemokine receptor CXCR6 in steady-state trafficking of influenza- specific memory CD8 T cells to the lung airways and to identify the factors that regulate CXCR6 expression. In addition to gaining insight to the role of CXCR6, it is hoped that these studies will create a platform to advance the field of prophylactic cell-mediated vaccines against respiratory pathogens and to develop novel therapeutic agents that promote pathogen-specific T cell recruitment to the lung airways; in this manner, such agents could enhance protective immunity to respiratory pathogens. Such advances would strengthen preventative care methods to impart a higher quality of life for patients. The proposed research project will serve as a framework for the applicant's training plan, which is specifically designed to integrate basic science research in pulmonary mucosal immunology with the applicant's career goal of becoming an independent physician scientist whose research focus will be viral mucosal immunology.
项目摘要 非常脆弱但高度结构化,肺部受到潜在病原体,过敏原和刺激物的攻击 每一次呼吸。流感病毒的年度流行是发病率和死亡率的重要来源, 对美国和全世界造成重大的健康障碍和沉重的经济负担。特别是 流感病毒潜伏期短,感染率高,传播迅速, 肺部合并症患者的护理。然而,效应记忆CD 8 T细胞的存在, 肺可以快速地控制病原体的局部扩散 肺部有害的广泛炎症反应。人类和动物模型的关键发现 研究表明,气道驻留记忆性CD 8 T(TARM)细胞的保护功效直接相关, 与流感攻击时存在于肺气道中的记忆性CD 8 T细胞的数量有关; TARM细胞数量下降,对流感攻击的保护也下降。然而,目前还不清楚TARM细胞是如何 维持在感染部位,即肺气道,在那里它们具有独特的位置,可以快速响应 流感感染。该过程的第一步是阐明这些存储器CD 8 T 细胞从全身循环进入肺。人们普遍认为,趋化因子受体和粘附 分子配对对于将驻留记忆性CD 8 T(TRM)细胞亚群运输到特定的外周血中是必需的 组织中虽然粘附分子已被确定,趋化因子受体所必需的稳态 记忆性CD 8 T细胞向肺部的募集则没有。这种特异性趋化因子受体的鉴定和 阐明调控其表达的机制是这一建议的基础。的目标 拟议的项目是确定趋化因子受体CXCR 6在流感稳态运输中的作用- 特异性记忆性CD 8 T细胞的肺气道和确定的因素,调节CXCR 6的表达。在 除了深入了解CXCR 6的作用外,还希望这些研究将创造一个平台, 针对呼吸道病原体的预防性细胞介导的疫苗领域以及开发新的治疗 促进病原体特异性T细胞募集到肺气道的试剂;以这种方式,这样的试剂可以 增强对呼吸道病原体的保护性免疫。这些进步将加强预防保健 为患者提供更高生活质量的方法。拟议的研究项目将作为框架 申请人的培训计划,这是专门设计的,以整合基础科学研究,在肺 粘膜免疫学,申请人的职业目标是成为一名独立的医生科学家, 研究重点是病毒粘膜免疫学。

项目成果

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