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.