Defining the Role of Persistent Antigen Presentation in CD8 T Cell Memory Develop

描述(由申请人提供)：发展有效的CD8T细胞记忆是疫苗接种的重要目标。尽管CD8T细胞有效地启动，但在急性呼吸道病毒感染清除后的几周内观察到持续的抗原提呈。然而，目前尚不清楚抗原是如何被保留的，或者持续性抗原提呈对CD8记忆T细胞功能的影响是什么。一些研究表明，连续的TCR刺激可能控制CD8记忆T表型和记忆回忆反应的质量。本研究的目标是在一种新的非感染性模型中确定保留和呈递持久抗原的细胞，并了解其在CD8T细胞记忆维持和回忆效能的发展和维持中的作用。具体目标1建议定义长寿抗原的细胞库。使用共聚焦显微镜跟踪标记的抗原，以及CD11c驱动的白喉毒素受体转基因和基因敲除小鼠模型，将测试FDC在保留持久抗原方面的作用。特定目的2建议定义持续性抗原提呈中的细胞参与者。活细胞分选和与转基因CD8 T细胞共培养将确定哪些抗原提呈细胞在体外呈现持久抗原。过继转移幼稚T细胞、效应记忆T细胞和中央记忆T细胞将决定哪些CD8 T细胞可以对持续性抗原提呈做出反应。具体目的3提出确定持续的IC呈现对CD8T细胞记忆的影响。基于流式细胞术的表型分析和重组病原体将被用来确定持续性抗原递呈对CD8T细胞记忆发育、维持和回忆功能的影响。拟议的研究结果将使我们了解CD8 T细胞生物学与疫苗开发的直接相关。

DESCRIPTION (provided by applicant): Development of effective CD8+ T cell memory is a significant goal of vaccination. Despite efficient CD8+ T cell priming, persistent antigen presentation has been observed for weeks following clearance of acute respiratory viral infections. However little is currently known about how antigen is retained, or what the consequence of persistent antigen presentation is on the function of CD8+ memory T cells. Several studies have suggested that serial TCR stimulation may control CD8+ memory T phenotype and the quality of the memory recall response. The goal of this research proposal is to define the cells retaining and presenting persistent antigen in a novel non- infectious model, as well as understand its role in the development and maintenance of CD8+ T cell memory maintenance and recall efficacy. Specific Aim 1 proposes to define the cellular depots of long-lived antigen. Using confocal microscopy to track labeled antigen, and CD11c-driven diptheria-toxin receptor transgenic and knockout mouse models, the role of FDC in retention of persistent antigen will be tested. Specific Aim 2 proposes to define the cellular participants in persistent antigen presentation. Live cell sorting and co-culture with transgenic CD8+ T cells will determine which antigen presenting cells presents persistent antigen ex vivo. Adoptive transfer of naive, effector memory, and central memory T cells will define which CD8+ T cells can respond to persistent antigen presentation. Specific Aim 3 proposes to determine the effect of persistent IC presentation on CD8+ T cell memory. Flow cytometery-based phenotypic analysis and recombinant pathogens will be used to determine the effects of persistent antigen presentation on CD8+ T cell memory development, maintenance, and recall functionality. The results of the proposed research will inform our understanding of CD8+T cell biology with direct relevance to vaccine development.