CD8 T Cell Response to Influenza Virus Infection

描述(申请人提供)：流感病毒，C类生物防御病原体，是一种临床上重要的感染性病原体，对人类健康有严重影响。大流行的威胁以及故意污染高致病性或基因工程病毒株的可能性，为进一步深入分析病毒控制的免疫机制提供了强有力的理由，这是本RFA的重点。虽然针对感染的疫苗接种被认为主要是通过诱导血清型特异性中和抗体来介导的，但CD8T细胞有可能对不同的病毒血清型提供广泛的有效性。我们的初步数据发现了一个新的记忆性CD8T细胞亚群，并提示记忆性CD8T细胞和B细胞之间存在潜在的联系。这些发现为这项旨在了解记忆CD8 T细胞亚群解剖定位的功能意义并确定其对流感病毒感染的保护能力的提议提供了基础。这项建议的具体目标是： 具体目的1.检测流感病毒感染后记忆性CD8 T细胞亚群的特性及其保护能力。流感病毒感染后形成的记忆性CD8T细胞群是异质性的，由基于表型和位置的多个亚群组成。我们的初步数据表明，通过识别一个新的B220+记忆性CD8 T细胞亚群，可能会增加复杂性。这一目标的实验将集中在记忆CD8 T细胞亚群的深入表型和功能特征上，包括测试它们发动二次反应和提供对流感病毒感染的保护的能力。 具体目的2.现场观察流感病毒感染后的初始反应和回忆反应。发生在原发或继发流感病毒感染的免疫应答过程中的解剖学事件尚未被描述。我们已经开发出技术，可以在感染后原位显示内源性抗原特异性的初级和记忆性CD8T细胞。初步数据表明，流感病毒感染后，在淋巴结和脾的B细胞区存在一种新的CD8记忆T细胞群，B220+记忆细胞是否优先定位于这些部位将进行测试。这一群体和其他记忆亚群对感染的反应行为也将被确定。这样，记忆亚群的保护能力和次级反应的解剖结构之间就建立了联系。总体而言，这些研究将填补我们对记忆CD8 T细胞在控制流感病毒感染中的作用的认识上的一个重大空白。

DESCRIPTION (provided by applicant): Influenza virus, a Category C Biodefense pathogen, is a clinically important infectious agent with serious implications for human health. The threat of a pandemic as well as the potential for intentional contamination with highly pathogenic or genetically engineered virus strains provide strong rationales for further in-depth analysis of the immune mechanisms of viral control, the focus of this RFA. While vaccination against infection is believed to be mediated primarily by induction of serotype-specific neutralizing antibody, CD8 T cells have the potential to provide broad-based effectiveness against distinct viral serotypes. Our preliminary data identifies a novel memory CD8 T cell subset and suggests a potential link between memory CD8 T cells and B cells. These findings provide the foundation for this proposal aimed at learning the functional significance of the anatomical localization of memory CD8 T cell subsets and determining their protective capacity against influenza virus infection. The specific aims of the proposal are: Specific Aim 1. To characterize memory CD8 T cell subsets and determine their protective ability following influenza virus infection. The memory CD8 T cell population that develops following influenza virus infection is heterogeneous and comprised of multiple subsets based on phenotype and location. Our preliminary data suggested additional complexity by identifying a novel B220+ memory CD8 T cell subset. Experiments in this aim will focus on an in-depth phenotypic and functional characterization of memory CD8 T cell subsets including testing their ability to mount secondary responses and provide protection against influenza virus infection. Specific Aim 2. To visualize the primary and recall response to influenza virus infection in situ. The anatomical events that occur in situ during the immune response to primary or secondary influenza virus infection have not been described. We have developed techniques to allow visualization of endogenous antigen-specific primary and memory CD8 T cells in situ following infection. Preliminary data identify a novel population of memory CD8 T cells residing in the B cell zones of the lymph nodes and spleen following influenza virus infection and whether B220+ memory cells preferentially localize to these sites will be tested. The behavior of this population and other memory subsets to respond to infection will also be determined. In this way, a link will be established between the protective capacity of memory subsets and the anatomy of the secondary response. Overall, these studies will fill a significant gap in our knowledge regarding the role of memory CD8 T cells in controlling influenza virus infection.