Cellular intermediates in stable memory CD8 T cell maintenance

描述（由申请人提供）：记忆性CD 8 T细胞的一个长期公认的特征是它们持续的、尽管缓慢的细胞因子驱动的增殖（所谓的“记忆周转”）。有趣的是，通过实验感染或疫苗接种产生的记忆性CD 8 T细胞群可以在实验室小鼠中长时间保持数量稳定，最近的证据表明，记忆性群体在人类中可以维持数十年。记忆性CD 8 T细胞群的稳定性可能是成功接种疫苗的关键因素，并且已经做出了很多努力来理解对于记忆维持至关重要的细胞因子（例如IL-7和IL-15）。然而，这些数据也提出了一个难题-如何保持稳定数量的记忆CD 8 T细胞在面对这个人口的持续增殖？ 显然，宿主必须有某种方法来“计数”记忆细胞的数量，以便通过等效死亡来平衡该群体的增殖。深入了解稳定记忆维持期间控制生命和死亡的机制不仅可以揭示免疫系统稳态的重要新元素，还可以提供增强疫苗诱导的记忆或改善老年人记忆衰退的方法。尽管这一领域的潜在重要性，但基本上没有实验数据来解决是否，如何以及何时选择CD 8 T细胞死亡以平衡记忆周转。很明显，这一领域的研究一直受到阻碍，因为缺乏识别在记忆转换过程中注定死亡的中间体的信息。 我们的长期目标是了解在稳定的记忆CD 8 T细胞维持过程中导致平衡的生命和死亡的分子介质。正如初步数据中所详述的，我们最近发现了一种新的CD 8 T细胞群，占记忆池的约20%。该群体的特征在于不能响应于抗原刺激产生效应细胞因子如IFN-3或不能响应于体内抗原再暴露而经历实质性增殖。重要的是，我们有直接的证据表明，这种新的群体可以从Tcm CD 8 T细胞在体内稳态增殖过程中产生。该R21应用的直接目标是测试这种新的记忆性CD 8 T细胞群代表T记忆性死亡中间体（Tmdi）的假设。我们将通过以下具体目标来解决这个假设：具体目标1。确定CD 62 LloCD 27 lo细胞因子非生产者群体是否是T记忆死亡中间体（Tmdi）。具体目标2。确定推定的T记忆死亡中间体（Tmdi）的分子特征。 公共卫生相关性： 记忆T细胞在感染或接种疫苗后产生，可以保护宿主免受相同病原体的再次感染。 有趣的是，记忆T细胞群经历了持续的 细胞分裂，但在很长一段时间内保持稳定的数量。 这项提案的目的是了解记忆T细胞群是如何“计数”的，以便这些信息可以用于增强疫苗接种后的免疫力。

DESCRIPTION (provided by applicant): One long recognized feature of memory CD8 T cells is their continued, albeit slow, cytokine driven proliferation (so called "memory turnover"). Interestingly, memory CD8 T cell populations generated by experimental infection or vaccination can remain stable in numbers for long time periods in laboratory mice and recent evidence shows that memory populations are maintained for decades in humans. The stability of memory CD8 T cell populations is likely a key element of successful vaccination and much effort has been directed at understanding the cytokines (such as IL-7 and IL-15) that are essential for memory maintenance. However, these data also raise a conundrum-how are stable numbers of memory CD8 T cells maintained in the face of continued proliferation of this population? Clearly the host must have some way of "counting" memory cell numbers such that the proliferation of this population is balanced by equivalent death. A deeper understanding of the mechanisms controlling life and death during stable memory maintenance could not only reveal important new elements of immune system homeostasis but also provide means to enhance vaccine- induced memory or improve declining memory in the elderly. Despite the potential importance of this area, there are essentially no experimental data to address if, how and when CD8 T cells are selected for death to balance memory turnover. It seems apparent that this area of research has been stymied for lack of information identifying intermediates that are destined to die during memory turnover. Our long-term goal is to understand the molecular mediators resulting in balanced life and death during stable memory CD8 T cell maintenance. As detailed in the preliminary data we recently identified a novel CD8 T cell population representing ~20% of the memory pool. This population is characterized by the inability to produce effector cytokines such as IFN-3 in response to antigen- stimulation or to undergo substantial proliferation in response to in vivo antigen re-exposure. Importantly, we have direct evidence that this novel population can be generated from Tcm CD8 T cells during homeostatic proliferation in vivo. The immediate goal of this R21application is to test the hypothesis that this novel memory CD8 T cell population represents the T memory death intermediate (Tmdi). We will address this hypothesis through the following specific aims: Specific Aim 1. Determine if CD62LloCD27lo cytokine non-producer populations are T memory death intermediates (Tmdi). Specific Aim 2. Determine the molecular signature of putative T memory death intermediates (Tmdi). PUBLIC HEALTH RELEVANCE: Memory T cells are generated after infections or vaccination and can protect the host from reinfection with the same pathogen. Interestingly, memory T cell populations undergo continual cell division but are maintained at stable numbers for long periods of time. The goal of this proposal is to understand how memory T cell populations are "counted" so that this information can be used to enhance immunity after vaccination.