Molecular mechanisms controlling differentiation of memory CD8 T cells

 描述（由申请人提供）：在感染或免疫后形成和维持记忆性CD 8 T细胞的能力是适应性免疫应答的标志，也是针对感染性疾病的保护性疫苗接种或癌症免疫治疗的一个基础。由于对感染的保护程度取决于病原体暴露时存在的记忆性CD 8 T细胞的功能特征（质量）和数量（数量），因此了解记忆性CD 8 T细胞库的生成，分化和维持机制对于我们设计最有效疫苗的能力至关重要。在我们对急性感染或免疫后产生的记忆性CD 8 T细胞的生物学理解方面取得了实质性进展。然而，尽管取得了这一进展，许多重要问题仍然存在。例如，记忆性CD 8 T细胞的上级保护能力与它们在淋巴和非淋巴器官中增加的丰度密切相关，因此，已经投入了大量努力来鉴定增加记忆性CD 8 T细胞绝对数量的策略。在这些策略中，经常使用初免-加强方案（或多抗原（Ag）刺激），因为它们能够引发大量记忆性CD 8 T细胞。重要的是，我们最近的研究表明，用Ag进行的每次额外的再刺激不仅导致随后的记忆性CD 8 T细胞群的增殖能力的进行性降低，而且还改变它们的表型、功能、收缩率、基础增殖和存活能力。有趣的是，这些功能变化与每次抗原接触后记忆CD 8 T细胞中的转录组多样化相关。然而，目前尚不清楚哪些关键分子介质负责这些功能变化。填补这一知识空白对于优化记忆CD 8 T细胞数量，同时保持影响保护的质量至关重要。 我们的长期目标是充分了解一次或多次Ag接触后产生的记忆CD 8 T细胞群的功能后果。这些信息将在制定最佳策略以产生和操纵响应于疫苗接种的保护性CD 8 T细胞介导的免疫方面具有重要意义。我们将检验总体假设，即银刺激的历史是控制功能和长期维持的关键决定因素。 记忆性CD 8 T细胞群。我们将开始通过以下具体目标来解决我们的长期目标-确定控制重复抗原遭遇后产生的记忆性CD 8 T细胞的分化和功能的分子机制。

 DESCRIPTION (provided by applicant): The ability to develop and sustain memory CD8 T cells after infection or immunization is a hallmark of the adaptive immune response and one basis for protective vaccination against infectious disease or in cancer immunotherapy. Since the degree of protection to infection depends on the functional characteristics (quality) and the number (quantity) of memory CD8 T cells present at the time of pathogen exposure, understanding the mechanisms that govern generation, differentiation and maintenance of the memory CD8 T cell pool are critical to our ability to design the most effective vaccines. Substantial progress has been made in our understanding of the biology of memory CD8 T cells generated after acute infection or immunization. However, despite this progress many important questions remain. For instance, the superior protective capacity of memory CD8 T cells is closely linked to their increased abundance in both lymphoid and non-lymphoid organs, and as a consequence much effort has been devoted to identifying strategies that increase the absolute numbers of memory CD8 T cells. Among these strategies, prime-boost regimes (or multiple antigen (Ag) stimulations) are often used because of their ability to elicit large numbers of memory CD8 T cells. Importantly, our recent studies demonstrated that each additional re-stimulation with Ag results not only in progressive decrease in proliferative capacity of the ensuing memory CD8 T cell populations but also change their phenotype, function, rate of contraction, basal proliferation and ability to survive. Interestingly, these functional changes ar associated with transcriptomic diversification in memory CD8 T cells after each antigen encounter. However, it is unknown which key molecular mediators are responsible for each of these functional changes. Filling this knowledge gap has critical importance in order to optimize memory CD8 T cell numbers while preserving qualities that impact protection. Our long-term goal is to fully understand the functional consequences imposed on memory CD8 T cell populations generated after one or more Ag encounters. This information will be significant in formulating the best strategies to generate and manipulate protective CD8 T cell-mediated immunity in response to vaccination. We will test the overall hypothesis that the history of Ag-stimulations is a critical determining factor controlling the function and long-term maintenance of memory CD8 T cell populations. We will begin to address our long- term goal through the following Specific Aim - Determine the molecular mechanisms controlling differentiation and function of memory CD8 T cells generated after repetitive antigen encounters.