Jm. Witkowski et Ra. Miller, Calcium signal abnormalities in murine T lymphocytes that express the multidrug transporter P-glycoprotein, MECH AGE D, 107(2), 1999, pp. 165-180
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.