CD8 T Cell Activation and Migration in Vivo

描述（由申请人提供）：CD8 T细胞是清除细胞内病原体所必需的。疫苗学目前的一个目标是开发方法，诱导保护性T细胞介导的反应，以对抗一些世界上最棘手的传染病，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细胞对强感染的反应是最好的情况，但这些模型已经对记忆性CD8 T细胞发育的调节产生了有价值的见解。到目前为止，旨在促进CD8 T细胞免疫的疫苗通常没有取得成功。因此，识别记忆CD8 T细胞发育中的检查点以及控制这些检查点的元素仍然是一个重要的研究目标。我们的研究重点是详细分析控制中枢和效应记忆CD8 T细胞产生的因素，以应对细菌和病毒感染。我们的研究结果以及其他一些研究小组的研究结果表明，在对感染的反应中，原始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。这项长期资助支持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），它产生记忆细胞，以及短期效应细胞（SLEC），至少在初级反应中，是一个终末谱系。这一建议旨在探索中心假设，即对记忆谱系的承诺是在EEC阶段指定的，并且EEC本身就其发展潜力而言是异质的。这一假设将在三个具体目标中进行检验：目标1。确定欧共体因应外部环境的发展潜力。目标2。确定早期效应细胞中导致记忆发育的代谢途径。目标3。确定指定效应亚群谱系发展的分子途径。

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.