We previously showed that an IL-2 mutant, Q126D, could induce T cells to proliferate to the same extent as wild-type IL-2 but was unable to sensitize T cells to activation-induced cell death (AICD). Here we show that the partial signaling of Q126D is attributable to its inability to up-regulate the IL-2 receptor alpha chain (CD25). IL-12, which can up-regulate CD25 expression, enhances the ability of Q126D to induce AICD sensitivity and proliferation. IL-12 synergism with Q126D is dependent on CD25 up-regulation because the synergism is absent in CD25-deficient T cells. Inhibition of IL-12-induced up-regulation of CD25 by a p38 mitogen-activated protein (MAP) kinase inhibitor, SB203580, also ablates the synergism between IL-12 and Q126D. Although CD25 is important for IL-2-induced proliferation and AICD sensitivity, it is not absolutely required because a high concentration of IL-2 can overcome the requirement for CD25. Under physiological concentrations of IL-2, CD25 expression is critical for the function of IL-2. IL-12 can enhance the function of IL-2 by up-regulating CD25 in a p38 MAP kinase-dependent manner.