INDUCTION OF SENSITIVITY TO ACTIVATION-INDUCED DEATH IN PRIMARY CD4(-A ROLE FOR INTERLEUKIN-2 IN THE NEGATIVE REGULATION OF RESPONSES BY MATURE CD4(+) T-CELLS() CELLS )

We examine the requirements for converting naive, mature CD4(+) cells from an activation-induced death (AID)-resistant to a -sensitive pheno type. Priming for sensitivity to AID can be divided into two steps. Th e first is a mitogen/CD3-dependent, cyclosporin-sensitive signal and t he second a cytokine-dependent, cyclosporin-insensitive one. Under the se conditions, interleukin (IL)-2, but not IL-4, IL-7 or IL-15, the re ceptors of which share a common receptor gamma chain, is capable of pr oviding the cytokine signal for inducing sensitivity to AID. Increased expression of the low-affinity IL-2R alpha chain (CD25) is associated with acquisition of AID sensitivity and antibodies to CD25 block acqu isition of AID sensitivity in the presence of IL-2. As with T cell hyb ridomas, AID is dependent on both CD95 and CD95 ligand (CD95L) express ion, but unlike hybridomas, the sensitive and resistant phenotypes of primary CD4(+) cells cannot be distinguished by levels of CD95 express ion, functional CD95L nor the fraction of cells in cycle. The results suggest that the unique function of IL-2 is to regulate proteins, eith er not important or constitutively regulated in T cell hybridomas, tha t are essential for cell-autonomous suicide of activated CD4(+) cells. These experiments provide a mechanism for the recent observations of chronic lymphoproliferation and autoimmune disease in mice with null m utations in IL-2 or CD25.