CD8 T Cell Activation and Migration in Vivo

描述(申请人提供)：CD8T细胞对于清除细胞内病原体是必不可少的。疫苗学目前的一个目标是开发方法来诱导保护性T细胞介导的反应，以对抗世界上一些最难治的传染病，包括疟疾和人类免疫缺陷病毒。有效的疫苗接种需要产生具有保护能力的长寿命记忆细胞。诱导CD8 T细胞对强有力的感染产生生产性反应是最好的情况，但这样的模型已经为记忆CD8 T细胞发育的调节提供了宝贵的见解。到目前为止，旨在促进CD8 T细胞免疫的疫苗通常还没有成功。因此，识别记忆性CD8 T细胞发育中的检查点以及控制这些检查点的因素仍然是一个重要的研究目标。我们的研究集中于对控制中央和效应记忆CD8T细胞在细菌和病毒感染时产生的因素的详细分析。我们的结果与其他一些小组的结果一起表明，感染后天然CD8 T细胞的激活导致了具有不同表型和功能特性的异质效应细胞群的产生。在这项长期资助的支持下，我们的初步和已发表的数据表明，早期效应细胞(EEC)群体是两个主要效应亚群的来源：记忆前体效应细胞(MPEC)和短期效应细胞(SLEC)，前者产生记忆细胞，后者至少在初级反应中是终末血统。这一建议旨在探索这一中心假设，即对记忆谱系的承诺是在EEC阶段指定的，而且EEC本身就其发展潜力而言是不同的。这一假说将在三个具体目标中进行检验：目标1。确定EEC对外部环境的反应的发展潜力。目的2.鉴定早期效应细胞中导致记忆发育的代谢途径。目的3.确定影响效应器亚群谱系发育的分子途径。

DESCRIPTION (provided by applicant): CD8 T cells are essential for clearance of intracellular pathogens. A current goal of vaccinology is to develop methods for inducing protective T cell mediated responses against some of the world's most intractable infectious diseases, including malaria and the human immunodeficiency virus. Effective vaccination requires the generation of long-lived memory cells with protective capabilities. Induction of a productive CD8 T cell response to robust infections represents a best case scenario but such models have yielded valuable insight into the regulation of memory CD8 T cell development. Thus far, vaccines geared toward promoting CD8 T cell immunity have generally not met with success. Therefore, identifying the checkpoints in memory CD8 T cell development along with the elements controlling those checkpoints continues to represent an important research goal. Our studies have focused on the detailed analysis of the factors that control the generation of central and effector memory CD8 T cells in response to bacterial and viral infections. Our results along with those from a number of other groups, have shown that activation of na¿ve CD8 T cells in response to infection results in the generation of a heterogeneous population of effector cells with distinct phenotypic and functional properties. Our preliminary and published data supported by this long-standing grant, indicate that a population of early effector cells (EEC) are the sourc of the two major effector subsets: memory-precursor effector cells (MPEC), which generate memory cells, and short-lived effector cells (SLEC) which, at least in a primary response, are a terminal lineage. This proposal is aimed at exploring the central hypothesis that commitment to the memory lineage is designated at the EEC stage and further that EEC are themselves heterogeneous with respect to their developmental potential. This hypothesis will be examined in three specific aims: Aim 1. To determine the developmental potential of EEC in response to the external milieu. Aim 2. To identify the metabolic pathways in early effector cells leading to memory development. Aim 3. To identify the molecular pathways that specify effector subset lineage development.