Calcium signal abnormalities in murine T lymphocytes that express the multidrug transporter P-glycoprotein

Previous work has established that aging in mice leads to an accumulation o f T cells that express high levels of P-glycoprotein, a plasma membrane pum p that mediates multiple drug resistance in tumor cells but whose function in normal T cells is still obscure. Pgp(+) cells seem to be functionally de fective: isolated from the CD4 memory population of young mice, they are un responsive to T cell receptor-dependent stimuli in tests for proliferation and cytokine production. The proliferative defect can? however, be overcome by exposure to PMA plus the calcium ionophore ionomycin, suggesting that t he Pgp+ cells may have a specific defect in calcium signal generation. We s how here that Pgp+ T cells, from young or old mice, do indeed show smaller changes in intracellular calcium ion concentration than Pgp(-) cells, when activated either by Con A, anti-CD3 antibodies, or ionomycin. The differenc e between Pgp(+) and Pgp(-) cells is apparent even in experiments on isolat ed CD4 memory T cells from young mice and thus is not simply a consequence of the age-dependent increase in memory cell numbers. Although the molecula r basis for the abnormality in calcium signal generation by Pgp(+) cells is still uncertain, our data suggest that the effect could be due to inter-su bset differences in levels of sorcin, a 22 kDa cytoplasmic protein that is co-expressed with P-glycoprotein in many tumor sells and which binds free c alcium ion with high affinity. Sorcin levels are higher in Pgp(+) CD4 cells than in Pgp(-) CD4 cells of young mice and increase with age in CD4 cells, consistent with the hypothesis that sorcin interferes with calcium signals in the age-sensitive Pgp(+) T cell subset. (C) 1999 Elsevier Science Irela nd Ltd. All rights reserved.