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

Abstract

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.

Altered Ca2+ Homeostasis in Immune Cells during Aging: Role of Ion Channels

“…Changes in Ca 2+ influx in aged T cells are also reported [ 66 , 67 ]; however, the influence of aging after TCR activation and the underlying molecular players are still under investigation. Following T cell activation in mice, several groups reported a decline in the Ca 2+ levels with age [ 68 , 69 ].…”

“…Despite the substantial literature on SOCE associated with T cell function, the changes in Ca 2+ homeostasis components and age-related changes in Ca 2+ entry are less well understood. We recently linked the aging-related reduction in Ca 2+ signals to reductions of the primary critical players in the Ca 2+ signaling pathway [ 66 ]. The reduced expression of STIM and Orai mRNA and proteins leads to reduced Ca 2+ entry.…”

“…The upregulation of the plasma membrane Ca 2+ ATPases 4 (PMCA4) contributes to faster extrusion in CD8 + T cells isolated from aged mice. Furthermore, these cells show a less efficient TCR-induced [Ca 2+ ] i mobilization and increased insensitivity to Ca 2+ fluctuations during cytotoxic activity [ 66 ].…”

“…Changes in the prevalence of distinct T cell subsets have already been studied extensively [ 17 , 62 , 66 , 194 ], however very little is known on functional alterations affecting activation and the underlying molecular mechanisms (not only) in aging. The influence of T cell activation by Ca 2+ influx regulated by K V 1.3 and IK Ca 1 potassium channels may alter T cell function during aging [ 195 ].…”

The Number and Position of Orai3 Units within Heteromeric Store-Operated Ca2+ Channels Alter the Pharmacology of ICRAC

“…In addition to forming homomeric Orai1 SOCE channels, Orai1 proteins multimerize with Orai family members Orai2 and Orai3 when overexpressed [14]. Endogenous heteromeric SOCE channels have been reported in different cell types [15][16][17][18][19][20][21][22]. Orai3 may be a negative modulator as, upon knockdown of Orai3, SOCE can be increased [15][16][17][18]23,24].…”