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

定义持续抗原呈递在 CD8 T 细胞记忆发育中的作用

• 批准号: 8199078
• 负责人: Erin Rebecca Williams
• 金额: $ 5.3万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8199078
• 关键词: Acute; Adoptive Transfer; Antigen Presentation; Antigen-Antibody Complex; Antigen-Presenting Cells; Antigens; B-Lymphocyte Subsets; CD11c Antigens; CD8B1 gene; Cell Separation; Cells; Cellular biology; Coculture Techniques; Confocal Microscopy; Data; Development; Exhibits; Follicular Dendritic Cells; Goals; Immunity; Immunization; Infection; Interferon Type II; Interleukin-2; Knockout Mice; Label; Lead; Life; MHC Class I Genes; Maintenance; Malaria; Mediating; Memory; Modeling; Participant; Peptide/MHC Complex; Peripheral; Phenotype; Process; Proliferating; Proteins; Recombinants; Research; Research Proposals; Role; SELL gene; Stimulus; T memory cell; T-Lymphocyte; Testing; Time; Tissues; Transgenic Mice; Transgenic Organisms; Vaccination; Virus Diseases; base; diphtheria toxin receptor; experience; granzyme B; lymph nodes; macrophage; memory recall; mouse model; novel; pathogen; protective efficacy; respiratory; respiratory virus; response; vaccine development

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.

描述（由申请人提供）：开发有效的 CD8+ T 细胞记忆是疫苗接种的一个重要目标。尽管有效的 CD8+ T 细胞启动，在急性呼吸道病毒感染清除后数周仍观察到持续的抗原呈递。然而，目前对于抗原如何保留，或者持续抗原呈递对 CD8+ 记忆 T 细胞的功能有何影响，目前知之甚少。多项研究表明，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定义在新型非感染性模型中保留和呈递持久抗原的细胞，并了解其在 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 建议定义长寿命抗原的细胞库。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，将测试 FDC 在保留持久抗原中的作用。具体目标 2 建议定义持续抗原呈递的细胞参与者。活细胞分选并与转基因 CD8+ T 细胞共培养将确定哪些抗原呈递细胞在体外呈递持久抗原。幼稚 T 细胞、效应记忆 T 细胞和中央记忆 T 细胞的过继转移将定义哪些 CD8+ T 细胞可以对持续抗原呈递作出反应。具体目标 3 建议确定持续 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。拟议研究的结果将有助于我们了解与疫苗开发直接相关的 CD8+T 细胞生物学。 公共卫生相关性：持续抗原呈递是一种很大程度上未表征的现象，在呼吸道病毒和疟疾感染后已被注意到。拟议的研究将为我们提供对 CD8+T 细胞免疫发展过程的基本了解，与有效的疫苗开发直接相关。