Significance of Calcium Signaling for Aging in Lymphocytes

细胞毒性T淋巴细胞（ctl）是适应性免疫反应的关键参与者。ctl使用两个主要途径来发挥其细胞毒性功能，穿孔蛋白依赖途径和死亡受体依赖途径。CTL杀伤机制的几个步骤需要或由Ca2+本身调节。人类淋巴细胞Ca2+内流的主要途径是通过钙释放激活钙（CRAC）通道介导的储存操作钙进入（SOCE）。与成年人相比，老年人体内和体外CTL功能发生改变，免疫反应随着年龄的增长而减弱。其潜在机制尚未完全了解。在过去的两年中，我们已经证明，与从成年小鼠分离的细胞相比，老年小鼠的CTL中Ca2+信号和ICRAC减少。mRNA分析显示，主要关键分子Orai和STIM的水平发生了变化。此外，从成年小鼠和老年小鼠分离的CTL在杀伤动力学和杀伤能力方面存在较大差异。基于初步工作，本项目的主要目标是解释成年小鼠和老年小鼠细胞毒性CD8+ T细胞的杀伤动力学差异，并揭示老年小鼠CD8+ T细胞中受损Ca2+信号的功能相关性。考虑到初步的工作，这两个目标可能是相互关联的，我们提出以下假设：CD8+ T细胞亚型代表的变化结合Ca2+信号传导的差异是杀伤动力学差异的原因。

Cytotoxic T lymphocytes (CTLs) are key players of the adaptive immune response. CTLs use two major pathways to exert their cytotoxic function, a perforin-dependent and a death receptor-dependent pathway. Several steps of the CTL killing machinery require or are modulated by Ca2+ itself. The major route of Ca2+ influx in human lymphocytes is through store-operated calcium entry (SOCE), mediated by calcium release-activated calcium (CRAC) channels. CTL function is altered in vivo and in vitro in elderly compared to adult individuals and the immune response is compromised with progressing age. The underlying mechanisms are not completely understood.During the last two years we have shown that in CTL from elderly mice Ca2+ signals and ICRAC are reduced compared to cells isolated from adult mice. The mRNA analysis revealed altered levels of the main key molecules, Orai and STIM. Furthermore, the CTL isolated from adult and elderly mice show large differences in killing kinetics and ability. Based on the preliminary work the main goals of this continued project are to explain the differences in killing kinetics between cytotoxic CD8+ T cells from adult and elderly mice and unmask the functional relevance of impaired Ca2+ signaling in CD8+ T cells from elderly mice. Considering the preliminary work, these two goals are likely linked with each other and we propose the following hypothesis: Changes in CD8+ T cell subtype representation combined with differences in Ca2+ signaling are responsible for the differences in killing kinetics.