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，但保护效果不佳，需要每年重新配制疫苗。由于中和的主要靶点（血凝素，HA和神经氨酸酶，NA）的高突变率以及其在非人类宿主中的重组能力，IAV可以逃避预先存在的抗体的中和。在缺乏中和抗体的情况下，记忆性CD8 t细胞特异性抗原表位位于IAV蛋白的保守区域，如内部成分核蛋白（NP）、聚合酶A和基质蛋白，可以赋予保护作用。最近在2009年H1N1流感病毒大流行期间进行的人体挑战研究和纵向分析支持这样一种观点，即当预先存在的抗体缺失时，交叉反应记忆CD8 T细胞能够改善疾病。由于大多数人类携带少量这种广泛保护性记忆CD8 t细胞，通过促进增加这些细胞的数量是增强其保护能力的一种有吸引力的策略。然而，记忆性CD8 t细胞构成了一个非常异质性的群体，对于增强或多重抗原暴露如何影响CD8 t细胞介导的抗IAV保护知之甚少。例如，我们最近报道了增强剂的类型显著影响所产生的记忆性CD8 t细胞群体的定位和保护能力（Sl - tter等人，2013）。因此，我们的长期目标是确定抗IAV的最佳记忆CD8 t细胞特性，并了解如何产生这样的记忆群。反过来，这些研究将为优化具有广泛保护性的疫苗提供关键信息

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.