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 of T cells that express high levels of P-glycoprotein, a plasma membrane pump that mediates multiple drug resistance in tumor cells but whose function in normal T cells is still obscure. Pgp+ cells seem to be functionally defective: isolated from the CD4 memory population of young mice, they are unresponsive 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 the Pgp+ cells may have a specific defect in calcium signal generation. We show 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 difference between Pgp+ and Pgp- cells is apparent even in experiments on isolated 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 molecular 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-subset differences in levels of sorcin, a 22 kDa cytoplasmic protein that is co-expressed with P-glycoprotein in many tumor cells and which binds free calcium 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.
Witkowski
J M
JM
Department of Physiopathology, Medical University of Gdansk, Poland.
Miller
R A
RA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000375:Aging / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000096:biosynthesis; D007156:Immunologic Memory; D051379:Mice; D008810:Mice, Inbred C57BL
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002135:Calcium-Binding Proteins; C503114:Sri protein, mouse