T lymphocyte activation and lnterleukln-2 (IL-2) production require at least two signals, generated by phorbol ester (TPA) and Caz+ ionophore or costimulatlon of the T cell receptor (TCR) and the CD28 auxiliary receptor. We investigated how these stimull affect mitogen activated protein (MAP) klnases. Full activation of the MAP kinases that phosphorylate the Jun actlvation domaln, JNKl and JNK2, required costimulatlon of T cells with either TPA and Caz+ ionophom or antibodies to TCR and CD28. Alone, each stimulus resulted In little or no activation. Similar to Its effect on IL-2 induction, cyclosporin A (CsA) Inhibited thesynerglstic activation of JNK, and a competitive inhibitor of Jun phosphorylatlon by JNK inhibited IL-2 promoter activation. By contrast, the MAP klnases ERKl and ERK2 were fully activated by TPA or TCR stimulation and were not affected by Caz+, CD28, or CsA. Hence, Integration of signals that lead to T cell activation occurs at the level of JNK activation.