Cellular intermediates in stable memory CD8 T cell maintenance

描述（由申请人提供）：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（即所谓的“记忆周转”）。有趣的是，在实验室小鼠中，由实验性感染或疫苗接种产生的记忆CD8 T细胞群可以在很长一段时间内保持数量稳定，最近的证据表明，人类的记忆群可以维持数十年。记忆性CD8 T细胞群的稳定性可能是成功接种疫苗的关键因素，人们已经努力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，记忆性CD8 T细胞的稳定数量是如何维持的？显然，宿主一定有某种“计数”记忆细胞数量的方法，这样，这个群体的增殖就会与等效的死亡相平衡。对稳定记忆维持过程中生死控制机制的深入了解，不仅可以揭示免疫系统稳态的重要新因素，还可以为增强疫苗诱导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解决CD8 T细胞是否、如何以及何时被选择死亡以平衡记忆更新。很明显，这一领域的研究一直受到阻碍，因为缺乏识别记忆转换过程中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平衡生与死的分子介质。正如初步数据所述，我们最近确定了一种新的CD8 T细胞群，占内存池的约20%。该人群的特点是不能产生效应细胞因子，如IFN-3，以应对抗原刺激或经历大量增殖，以应对体内抗原再暴露。重要的是，我们有直接证据表明，这种新的群体可以在体内稳态增殖过程中由Tcm CD8 T细胞产生。这个r21应用的直接目标是测试这种新的记忆CD8 T细胞群代表T记忆死亡中间体（Tmdi）的假设。我们将通过以下具体目标来解决这一假设：确定CD62LloCD27lo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。确定假定的T记忆死亡中间体（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). 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.