A MECHANISM OF RETINOID POTENTIATION OF MURINE T-CELL RESPONSES - EARLY UP-REGULATION OF INTERLEUKIN-2 RECEPTORS

The capacity of retinoids to amplify the proliferative response of BAL B/c lymphocytes to concanavalin A (Con A)2 in the presence of exogenou s interleukin-2 (IL-2) and the induction of IL-2 receptors (IL-2R) on L3T4- and Lyt-2+ T-cells was evaluated. Preincubation with Con A for 8 h in the presence of retinoids resulted in a greater than two-fold in crease in spleen cell proliferative response to Con A plus rIL-2 over the following 72 h relative to the response of cells preincubated with Con A alone. Peak potentiation of IL-2 responses occurred over a phar macologic range of retinoic acid (RA) concentration (10(-10)-10(-8) M) in the presence of 20 U/ml rIL-2. This potentiation of the response t o IL-2 was likewise observed after 8 h prestimulation with Con A with splenic T-cells enriched by passage over nylon wool. Preincubation of the spleen cells with Con A plus RA without the subsequent addition of IL-2 resulted in a proliferative response that was potentiated nearly to the level of the response produced by subsequent addition of IL-2 to Con A-activated cells. Preincubation of the cells with Con A in the presence of RA produced a true synergy with IL-2; the resulting incre ase in response was greater than the sum of the increases produced by RA or IL-2 alone. By assessing the proportion of cells that became IL- 2R positive during the early phase of cell activation by Con A and RA, it was determined that this augmentation by RA was apparently associa ted with increased IL-2R expression among L3T4+ (CD4), Lyt-2+ (CD8) an d total T-cells. Indeed, RA-induced proliferative increases were signi ficantly inhibited by addition to culture of anti-IL-2R antibodies. Th e potentiation of IL-2R expression by RA occurred early during Con A-a ctivation suggesting that the kinetics of IL-2R expression were increa sed by RA. Indeed, near-maximal IL-2R expression was observed after a 12 h stimulation in the presence of RA, whereas maximal IL-2R expressi on in cultures containing only Con A occurred after 24 h. IL-2R expres sion was potentiated by RA in both CD4 and CD8 T-cells, but was potent iated more rapidly in the CD4 subpopulation. These data suggest that a t least one of the mechanisms underlying retinoid potentiation of T-ce ll proliferation is the retinoid-induced increase in the rate of IL-2R expression.