Significance of Calcium Signaling for Aging in Lymphocytes

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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.