Memory CD8 T cell localization and protection from influenza

描述（由申请人提供）：流感病毒感染对人类健康有重大影响，大流行感染的威胁仍然迫在眉睫。抗体诱导甲型流感病毒（IAV）疫苗是可用的，但保护是次优的，需要每年重新配制疫苗。IAV可以逃避预先存在的抗体的中和，这是由于中和的主要靶标（血凝素，HA和神经氨酸酶，NA）的高突变率以及由于其在非人宿主中重组的能力。在不存在中和抗体的情况下，对位于IAV蛋白的保守区域中的表位（如内部组分核蛋白（NP）、聚合酶A和基质蛋白）具有特异性的记忆CD8 T细胞可以赋予保护。在2009年H1N1 IAV大流行期间，最近的人类挑战研究和纵向分析支持交叉反应性记忆CD8 T细胞能够在预先存在的抗体不存在时改善疾病的观点。由于大多数人携带少量这些广泛保护性记忆CD8 T细胞，因此通过增强来增加这些细胞的数量是一种有吸引力的策略，以增强其保护能力。然而，记忆性CD8 T细胞构成了一个非常异质的群体，关于加强或多种抗原暴露如何影响CD8 T细胞介导的抗IAV保护作用知之甚少，例如，我们最近报道了加强剂的类型显著影响所得记忆性CD8 T细胞群体的定位和保护能力（Sletter et al，2013）。因此，我们的长期目标是确定最佳的记忆CD8 T细胞特征，以保护免受IAV的侵害，并了解如何产生这种记忆群体。反过来，这些研究将提供关键信息，以优化广泛的保护性疫苗， IAV具体目标1。 确定调节记忆性CD8 T细胞中CXCR3表达以增强气道定位的分子机制。 具体目标2。确定反复IAV感染对气道监视、组织驻留和循环记忆CD8 T细胞产生的影响，以及它们在预防IAV中的相对作用。

DESCRIPTION (provided by applicant): Influenza virus infections have a major impact on human health and the threat of pandemic infections remains imminent. Antibody inducing Influenza A virus (IAV) vaccines are available, however protection is suboptimal and requires annual reformulation of the vaccine. IAV can escape neutralization by preexisting antibodies due to the high rate of mutation in the primary targets of neutralization (hemagglutinin, HA and neuraminidase, NA) and due to its capacity to recombine in non-human hosts. In the absence of neutralizing antibodies, memory CD8 T-cell specific for epitopes located in conserved regions of IAV proteins like the internal components nucleoprotein (NP), polymerase A and matrix protein can confer protection. Recent human challenge studies and longitudinal analyses during the 2009 H1N1 IAV pandemic support the notion that cross-reactive memory CD8 T cells are capable of ameliorating disease when pre-existing antibodies are absent. As most humans carry a small number of these broadly protective memory CD8 T-cells, increasing the number of these cells through boosting is an attractive strategy to bolster their protective capacity. However, memory CD8 T-cells constitute a very heterogeneous population and little is known about how boosting or multiple antigen exposures effects CD8 T-cell mediated protection against IAV, For instance, we have recently reported that the type of booster agent significantly affects the localization and protective capacity of the resulting memory CD8 T-cell population (Sl�tter et al, 2013). Therefore, our long-term goal is to determine optimal memory CD8 T-cell characteristics for protection against IAV and to understand how such memory populations can be generated. In turn, these studies will provide crucial information to optimize broadly protective vaccines for IAV. Specific Aim 1. Determine the molecular mechanisms regulating CXCR3 expression in memory CD8 T cells to enhance airway localization. Specific Aim 2. Determine the impact of repetitive IAV infections on the generation of airway---surveilling, tissue resident and circulatin memory CD8 T cells and their relative contribution in protection from IAV.