We examined 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, IL2, and not several other cytokines sharing a common receptor chain (IL-4, IL-7, IL-15), is uniquely capable of providing the cytokine signal for inducing sensitivity to AID. Increased expression of the low affinity IL-2R (CD25) is associated with acquisition of the AID sensitive phenotype and antibodies to CD25 can block acquisition of the sensitive phenotype in the presence of IL-2. As with T cell hybridomas, AID is dependent on both CD95 and 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.
|State||Published - Dec 1 1996|