Increased function of P-glycoprotein in T lymphocyte subsets of aging mice.
The age-associated decline in T lymphocyte function can be attributed in part to shifts between subsets (in particular the accumulation of memory T cells at the expense of naive T cells), and in part to alterations of function within the different T lymphocyte subsets. We show that the fluorochrome rhodamine-123 (R123) can distinguish further subdivisions within the naive and memory populations of both CD4 and CD8 T cells in the mouse. Aging leads to a progressive increase in the proportion of T cells in each subset that stain dimly with R123, and a corresponding decrease in the proportion of R123hi T cells, which are typical in young mice. We show that differential R123 staining between T cell subsets is due to variation in the activity of P-glycoprotein (P-Gp), the 170 kDa, ATP-dependent plasma membrane pump that mediates multiple-drug resistance. All T cells initially take up equivalent amounts of R123, but some T cells then can extrude the dye in a temperature-dependent process that is blocked by each of four pharmacologically disparate inhibitors of P-Gp function. Immunofluorescence experiments suggest that T cells from old and young mice have equal amounts of the P-Gp molecule itself, suggesting that differences in R123 extrusion may depend on posttranslational regulation of P-Gp activity.
Witkowski
J M
JM
Department of Pathology, University of Michigan School of Medicine, Ann Arbor 48109.
Miller
R A
RA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000375:Aging; D000818:Animals; D001692:Biological Transport; D007156:Immunologic Memory; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D012235:Rhodamines / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008562:Membrane Glycoproteins; D012235:Rhodamines