Cellular intermediates in stable memory CD8 T cell maintenance

描述(申请人提供)：记忆性CD8 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，由实验感染或疫苗接种产生的记忆CD8 T细胞群体在实验室小鼠中可以在很长一段时间内保持数量稳定，最近的证据表明，人类的记忆群体保持了数十年。记忆CD8 T细胞群的稳定性可能是成功接种疫苗的关键因素，人们一直致力于了解对记忆维持至关重要的细胞因子(如IL-7和IL-15)。然而，这些数据也提出了一个难题--面对这一群体的持续增殖，如何保持稳定数量的记忆CD8 T细胞？显然，宿主必须有某种方法来“计算”记忆细胞的数量，以便通过等量的死亡来平衡这一群体的增殖。深入了解稳定记忆维持过程中的生死控制机制，不仅可以揭示免疫系统动态平衡的重要新因素，还可以为增强疫苗诱导的记忆或改善老年人记忆衰退提供手段。尽管这一领域具有潜在的重要性，但基本上没有实验数据来说明CD8 T细胞是否、如何以及何时被选择死亡来平衡记忆周转。显然，这一领域的研究一直受到阻碍，因为缺乏识别在记忆周转期间注定会死亡的中间体的信息。我们的长期目标是了解在稳定记忆CD8 T细胞维持过程中导致生死平衡的分子介质。在初步数据中，我们最近发现了一种新的CD8T细胞群，约占内存池的20%。这一群体的特点是不能产生效应性细胞因子，如干扰素-3，以应对抗原刺激或在体内抗原再暴露时进行实质性增殖。重要的是，我们有直接证据表明，这种新的群体可以产生自中医CD8 T细胞在体内的动态平衡增殖。这个R21应用程序的直接目标是测试这个新的记忆性CD8 T细胞群体代表T记忆性死亡中间体(TMDI)的假设。我们将通过以下特定目标来解决这一假说：特定目标1.确定CD62LloCD27lo细胞因子非生产者群体是否为T记忆死亡中间体(TMDI)。特定目的2.确定可能的T记忆死亡中间产物(TMDI)的分子特征。

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).