Significance of Calcium Signaling for Aging in Lymphocytes

细胞毒性T淋巴细胞（CTL）是适应性免疫应答的关键参与者。CTL使用两种主要途径来发挥其细胞毒性功能，穿孔素依赖性途径和死亡受体依赖性途径。CTL杀伤机制的几个步骤需要或由Ca2+本身调节。人淋巴细胞内Ca2+内流的主要途径是通过钙释放激活的钙通道（CRAC）介导的钙库操纵的钙内流（SOCE）。与成年个体相比，老年人体内和体外CTL功能发生改变，并且随着年龄的增长，免疫应答受到损害。在过去的两年中，我们已经表明，在从老年小鼠的CTL的Ca 2+信号和ICRAC相比，从成年小鼠分离的细胞减少。mRNA分析揭示了主要关键分子奥赖和STIM的水平改变。此外，从成年和老年小鼠中分离的CTL在杀伤动力学和能力方面表现出很大差异。基于前期工作，该持续项目的主要目标是解释来自成年和老年小鼠的细胞毒性CD8+ T细胞之间的杀伤动力学差异，并揭示老年小鼠CD8+ T细胞中受损的Ca2+信号传导的功能相关性。考虑到初步的工作，这两个目标可能是相互联系的，我们提出了以下假设：CD8+ T细胞亚型代表的变化与Ca2+信号的差异相结合，是造成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.