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

项目摘要 肺非常脆弱，但高度结构化，受到潜在病原体、过敏原和刺激物的攻击 伴随着每一次呼吸。流感病毒每年的流行是发病率和死亡率的重要来源， 给美国和世界带来了沉重的经济负担，构成了一个重大的健康障碍。值得注意的是， 短潜伏期、高感染率和流感病毒的快速传播是独一无二的复杂因素 肺部合并症患者的护理。然而，效应记忆CD8 T细胞的存在 肺部可以迅速控制病原体的局部传播，同时减轻不受欢迎的和潜在的 肺部有害的广泛性炎症反应。来自人类和动物模型的主要发现 研究表明，呼吸道驻留记忆CD8 T(TARM)细胞的保护效果与 与流感发作时肺内存在的记忆CD8 T细胞的数量有关； TARM细胞数量下降，抵御流感挑战的保护力也下降。然而，尚不清楚TARM细胞是如何 维持在感染部位的肺气道，在那里它们具有独特的位置，可以迅速做出反应 一场流感感染。这个过程的第一步是阐明这些记忆CD8 T 细胞从全身循环进入肺部。趋化因子受体和黏附是公认的 分子对是将常驻记忆CD8T(TRM)细胞亚群运送到特定外周血细胞所必需的 纸巾。虽然黏附分子已经被确定，但稳定状态所必需的趋化因子受体 记忆性CD8 T细胞的募集并没有进入肺部。这一特异性趋化因子受体的鉴定和 阐明调节其表达的机制是这一提议的基础。的目标是 拟议的项目是确定趋化因子受体CXCR6在流感稳态传播中的作用。 特异性记忆CD8 T细胞到肺气道，并找出调节CXCR6表达的因素。在……里面 除了深入了解CXCR6的作用外，希望这些研究将创建一个平台，以推动 呼吸道病原体细胞介导型预防性疫苗研究领域及治疗新药的开发 促进病原体特异性T细胞向肺部呼吸道募集的药物；通过这种方式，这种药物可以 增强对呼吸道病原体的保护性免疫。这样的进步将加强预防性护理 方法提高患者的生活质量。拟议的研究项目将作为一个框架 申请人的培训计划，该计划是专门为整合肺科基础科学研究而设计的 黏膜免疫学申请人的职业目标是成为一名独立的内科科学家，其 研究重点将是病毒粘膜免疫学。

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.