EXTRUSION OF THE P-GLYCOPROTEIN SUBSTRATE RHODAMINE-123 DISTINGUISHESCD4 MEMORY T-CELL SUBSETS THAT DIFFER IN IL-2-DRIVEN IL-4 PRODUCTION

Approximately 25% of T cells in young mice are able to extrude the flu orescent P glycoprotein substrate Rhodamine-123 (R123), and these R123 (low) cells are present within the naive and memory cell populations o f both CD4 and CD8 type. The proportion of R123(low) T cells increases with age to approximately 60% in mice older than 18 mo of age. CD4 me mory T cells from young mice secrete more IL-4 compared with cells fro m old donors when activated by anti-CD3 and further cultured for 7 to 10 days in the presence of IL-2. To determine whether this age-related decline in IL-4 production was related to the parallel accumulation o f R123(low) T cells within the CD4 memory subset, we compared IL-4 pro duction in cell preparations enriched for R123(high) and R123(low) cel ls by electronic cell sorting. IL-2-driven IL-4 production by CD3-acti vated CD4 memory cells was found to be limited almost entirely to the R123(high) subset, i.e., the subset that declines with age. Proliferat ion under these culture conditions also declined with age and was also much more vigorous in R123(high) than in R123(low) cells. Not all R12 3(low) T cells, however, were resistant to IL-2-dependent proliferatio n and differentiation: limit dilution analyses showed nearly equal pro portions of Con A-responsive proliferative and cytotoxic clones within the R123(high) and R123(low) subsets of CD8 naive cells. These data s how that P glycoprotein-mediated extrusion of R123 delineates CD4 memo ry T cell subsets that differ in function. Although the loss with age in R123(high) T cells contributes to the decline in IL-2-driven IL-4 p roduction, aging also leads to diminished responsiveness even within t he remaining population of R123(high) CD4 memory cells.