QUIESCENCE-INDUCING AND ANTIAPOPTOTIC ACTIVITIES OF IL-15 ENHANCE SECONDARY CD4(-CELL RESPONSIVENESS TO ANTIGEN() T)

IL-15 shows functional redundancy with IL-2 due to its usage of the be ta and gamma(c) subunit of the IL-2R, Yet, the requirement of IL-15 fo r an IL-15R alpha chain for high affinity interaction and the separate cellular sources of IL-2 and IL-15 suggest divergent activities for b oth cytokines, We compared the growth-inducing and proapoptotic or ant iapoptotic activities of IL-15 and IL-2 on mature CD4(+) T lymphocytes in the presence or absence of TCR occupancy. We found that the nature of IL-15 activity was critically dependent on the activation status o f the T cells. In the absence of TCR triggering, IL-15 did not exert-t he growth factor activity of IL-2, but induced a quiescent phenotype, characterized by maintenance of the cells in the G(0)/G(1) phase of th e cell cycle and down-regulation of CD25, CD71, and CD95 expression, I n the presence of appropriate TCR engagement, the IL-15-induced quiesc ent T cells were resistant against TCR-induced cell death and prolifer ated strongly. IL-2-treated cells, on the contrary, were sensitized to cell death, resulting in a negative feedback on cellular expansion an d weak proliferative responsiveness. Consecutive action of IL-15 durin g the distinct phases of an in vitro immune response markedly increase d the cell output of a second antigenic stimulation, as compared with IL-2, These results imply that during immune reactivity in vivo, IL-15 may take over from the transiently available IL-2 the role of surviva l factor but not of growth factor, hence promoting the long term maint enance of resting, Ag-experienced CD4(+) T cells.