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

描述（由申请方提供）：有效CD8+ T细胞记忆的形成是疫苗接种的重要目标。尽管有效的CD8+ T细胞引发，但在急性呼吸道病毒感染清除后数周内观察到持续的抗原呈递。然而，目前对抗原是如何保留的，或者持续抗原呈递对CD8+记忆T细胞功能的影响知之甚少。一些研究表明，连续TCR刺激可以控制CD8+记忆T表型和记忆回忆反应的质量。本研究提案的目标是在新型非感染性模型中定义保留和呈递持久性抗原的细胞，以及了解其在CD8+ T细胞记忆维持和回忆功效的发展和维持中的作用。具体目标1提出定义长寿命抗原的细胞库。将使用共聚焦显微镜追踪标记抗原，以及CD11c驱动的白喉毒素受体转基因和敲除小鼠模型，检测FDC在持久性抗原保留中的作用。具体目标2提出定义持续抗原呈递中的细胞参与者。活细胞分选和与转基因CD8+ T细胞共培养将确定哪种抗原呈递细胞离体呈递持久性抗原。初始T细胞、效应记忆T细胞和中枢记忆T细胞的连续转移将确定哪些CD8+ T细胞可以响应持续抗原呈递。具体目标3提出确定持续IC呈递对CD8+ T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用于确定持续抗原呈递对CD8+ T细胞记忆发育、维持和回忆功能的影响。拟议研究的结果将为我们了解与疫苗开发直接相关的CD8+T细胞生物学提供信息。 公共卫生相关性：持续性抗原呈递是在呼吸道病毒和疟疾感染后注意到的一种基本上未表征的现象。拟议的研究将告知我们对CD8+T细胞免疫发展过程的基本理解，与有效疫苗开发直接相关。

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. PUBLIC HEALTH RELEVANCE: Persistent antigen presentation is a largely uncharacterized phenomenon that has been noted following both respiratory virus and malaria infection. The proposed research will inform our basic understanding of this process in development of CD8+T cell immunity, with direct relevance to effective vaccine development.