We examine the requirements for converting naive, mature CD4+ cells from an activation-induced death (AID)-resistant to a -sensitive phenotype. Priming for sensitivity to AID can be divided into two steps. The first is a mitogen/CD3-dependent, cyclosporin-sensitive signal and the second a cytokine-dependent, cyclosporin-insensitive one. Under these conditions, interleukin (IL)-2, but not IL-4, IL-7 or IL-15, the receptors of which share a common receptor gamma chain, is capable of providing 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 acquisition of AID sensitivity in the presence of IL-2. As with T cell hybridomas, AID is dependent on both CD95 and CD95 ligand (CD95L) expression, but unlike hybridomas, the sensitive and resistant phenotypes of primary CD4+ cells cannot be distinguished by levels of CD95 expression, functional CD95L nor the fraction of cells in cycle. The results suggest that the unique function of IL-2 is to regulate proteins, either not important or constitutively regulated in T cell hybridomas, that 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 mutations in IL-2 or CD25.