Fas-dependent, activation-induced death (AID) of T cells has been implicated in the regulation of peripheral T cell populations. We have previously reported that IL-2 plays a unique role in regulating sensitivity to AID in primary CD4+ cells. In this report we have compared the capacity of IL-2, IL-4, and IL-7 to increase entry into cell cycle vs their capacity to increase sensitivity to AID. Our data indicate that IL-2 plays a unique role in the regulation of AID in both Th1 and Th2 subsets and that with a given AID stimulus, cell cycle progression is necessary, but not sufficient, for AID. Interestingly, induction of cell cycle entry and sensitivity to AID can be dissociated (partial signaling) not only with different cytokines, but even with point mutations in IL-2 itself. This provides the first evidence that cytokine variants or pharmacological agents that mimic their action will be useful in enhancing selective elements of pleiotropic cytokine actions.