p38 mitogen-activated protein kinase mediates signal integration of TCR/CD28 costimulation in primary murine T cells

Optimal T cell activation requires two signals, one generated by TCR and an other by the CD28 costimulatory receptor, In this study, we investigated th e regulation of costimulation-induced mitogen-activated protein kinase (MAP K) activation in primary mouse T cells. In contrast to that reported for hu man Jurkat T cells, we found that p38 MAPK, but not Jun NH2-terminal kinase (JNK), is weakly activated upon stimulation with either anti-CD3 or anti-C D28 in murine thymocytes and splenic T cells, However, p38 MAPK is activate d strongly and synergistically by either CD3/CD28 coligation or PMA/Ca2+ io nophore stimulation, which mimics TCR-CD3/CD28-mediated signaling, Activati on of p38 MAPK correlates closely with the stimulation of T cell proliferat ion. In contrast, PMA-induced JNK activation is inhibited by Ca2+ ionophore . T cell proliferation and production of IL-2, IL-4, and IFN-gamma induced by both CD3 and CD3/CD28 ligation and the nuclear expression of the c-Jun a nd ATF-2 proteins are each blocked by the p38 MAPK inhibitor SB203580, Our findings demonstrate that p38 MAPK 1) plays an important role in signal int egration during costimulation of primary mouse T cells, 2) may be involved in the induction of c-Jun activation and augmentation of AP-I transcription al activity, and 3) regulates whether T cells enter a state of functional u nresponsiveness.