T lymphocyte activation and interleukin-2 (IL-2) production require at least two signals, generated by phorbol ester (TPA) and Ca2+ ionophore or costimulation of the T cell receptor (TCR) and the CD28 auxiliary receptor. We investigated how these stimuli affect mitogen activated protein (MAP) kinases. Full activation of the MAP kinases that phosphorylate the Jun activation domain, JNK1 and JNK2, required costimulation of T cells with either TPA and Ca2+ ionophore 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 the synergistic activation of JNK, and a competitive inhibitor of Jun phosphorylation by JNK inhibited IL-2 promoter activation. By contrast, the MAP kinases ERK1 and ERK2 were fully activated by TPA or TCR stimulation and were not affected by Ca2+, CD28, or CsA. Hence, integration of signals that lead to T cell activation occurs at the level of JNK activation.
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Correspondence should be addressed to M. K. We thank Drs. A. Alt-man, S. Hedrick, T. Hunter, and S. Swain for helpful discussions and critical comments that improved this manuscript. We thank Dr. R. Flavell for communication of unpublished results, and Drs. R. Davis, B. Derijard, A. Altman, G. Crabtree, M. Cobb, ht. Green, C. June, P. Linsley, M. Weber, T. Deng, and J. Hagstrom for the gifts of various reagents that made this work possible. We also thank C. Van Orshoven for dedicated secretarial assistance. Work was supported by grants from the American Cancer Society (MG#20) and National Institutes of Health (Ca-50528). B. S. and M. H. were supported by postdoctoral fellowships from the Irvington Institute, Cancer Research Institute and Japan Society for the Promotion of Science, respectively. E. J. was supported by a minority supplement to TRDRP grant 3RT-0138, and Y. B.-N. was supported by an American Cancer Society International Cancer Research Fellowship from the International Union against Cancer.