Orai, STIM, and PMCA contribute to reduced calcium signal generation in CD8+ T cells of elderly mice

Ca 2+ is a crucial second messenger for proper T cell function. Considering the relevance of Ca 2+ signals for T cell functionality it is surprising that no mechanistic insights into T cell Ca 2+ signals from elderly individuals are reported. The main Ca 2+ entry mechanism in T cells are STIM-activated Orai channels. Their role during lymphocyte aging is completely unknown. Here, we report not only reduced Ca 2+ signals in untouched and stimulated, but also in central and effector memory CD8 + T cells from elderly (18-24 months) compared to adult (3-6 months) mice. Two mechanisms contribute to the overall reduction in Ca 2+ signals of CD8 + T cells of elderly mice: 1) Reduced Ca 2+ currents through Orai channels due to decreased expressions of STIMs and Orais. 2) A faster extrusion of Ca 2+ owing to an increased expression of PMCA4. The reduced Ca 2+ signals correlated with a resistance of the cytotoxic efficiency of CD8 + T cells to varying free [Ca 2+ ] ext with age. In summary, reduced STIM/Orai expression and increased Ca 2+ clearing rates following enhanced PMCA4 expression contribute to reduced Ca 2+ signals in CD8 + T cells of elderly mice. These changes are apparently relevant to immune function as they reduce the Ca 2+ dependency of CTL cytotoxicity.