Research Paper Volume 12, Issue 4 pp 3266—3286
Orai, STIM, and PMCA contribute to reduced calcium signal generation in CD8+ T cells of elderly mice
- 1 Biophysics, Center for Integrative Physiology and Molecular Medicine, School of Medicine, Saarland University, Homburg 66421, Germany
- 2 Molecular Biophysics, Center for Integrative Physiology and Molecular Medicine, School of Medicine, Saarland University, Homburg 66421, Germany
- 3 Cellular Neurophysiology, Center for Integrative Physiology and Molecular Medicine, School of Medicine, Saarland University, Homburg 66421, Germany
- 4 Present address: Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Vienna 1090, Austria
Received: June 27, 2019 Accepted: January 24, 2020 Published: February 12, 2020
https://doi.org/10.18632/aging.102809How to Cite
Copyright © 2020 Angenendt et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Ca2+ is a crucial second messenger for proper T cell function. Considering the relevance of Ca2+ signals for T cell functionality it is surprising that no mechanistic insights into T cell Ca2+ signals from elderly individuals are reported. The main Ca2+ entry mechanism in T cells are STIM-activated Orai channels. Their role during lymphocyte aging is completely unknown. Here, we report not only reduced Ca2+ 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 Ca2+ signals of CD8+ T cells of elderly mice: 1) Reduced Ca2+ currents through Orai channels due to decreased expressions of STIMs and Orais. 2) A faster extrusion of Ca2+ owing to an increased expression of PMCA4. The reduced Ca2+ signals correlated with a resistance of the cytotoxic efficiency of CD8+ T cells to varying free [Ca2+]ext with age. In summary, reduced STIM/Orai expression and increased Ca2+ clearing rates following enhanced PMCA4 expression contribute to reduced Ca2+ signals in CD8+ T cells of elderly mice. These changes are apparently relevant to immune function as they reduce the Ca2+ dependency of CTL cytotoxicity.
Abbreviations
AM: acetoxymethyl ester; ATP: adenosine triphosphate; BAPTA: 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid; Ca2+: calcium; [Ca2+]int: internal Ca2+ concentration; [Ca2+]ext: external Ca2+ concentration; CTL: cytotoxic T lymphocyte; EGTA: ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid; ER: endoplasmic reticulum; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; HEPES: 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid; HPRT1: hypoxanthine phosphoribosyltransferase 1; IP3: inositol 1,4,5-trisphosphate; PMCA: plasma membrane Ca2+ ATPase; SDS-PAGE: sodium dodecyl sulfate–polyacrylamide gel electrophoresis; SERCA: sarco/endoplasmic reticulum Ca2+ ATPase; SOCE: store operated Ca2+ entry; STIM: stromal interaction molecule; TG: thapsigargin; TRPM: transient receptor potential melastatin.