p38 Mitogen-Activated Protein Kinase Mediates Signal Integration of TCR/CD28 Costimulation in Primary Murine T Cells

• Published in: The Journal of immunology (1950) Vol. 162; no. 7; pp. 3819 - 3829
• Main Authors: Zhang, Jian, Salojin, Konstantin V, Gao, Jian-Xin, Cameron, Mark J, Bergerot, Isabelle, Delovitch, Terry L
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01.04.1999
• Subjects: Activating Transcription Factor 2; Animals; Calcium - physiology; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; CD28 Antigens - immunology; CD3 Complex - immunology; CD3 Complex - metabolism; Cell Nucleus - drug effects; Cell Nucleus - enzymology; Cell Nucleus - metabolism; Cells, Cultured; Cyclic AMP Response Element-Binding Protein - antagonists & inhibitors; Cyclic AMP Response Element-Binding Protein - biosynthesis; Cytokines - antagonists & inhibitors; Cytokines - secretion; Drug Synergism; Enzyme Activation; Humans; Imidazoles - pharmacology; JNK Mitogen-Activated Protein Kinases; Jurkat Cells; Lymphocyte Activation - drug effects; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Proto-Oncogene Proteins c-jun - antagonists & inhibitors; Proto-Oncogene Proteins c-jun - biosynthesis; Pyridines - pharmacology; Receptors, Antigen, T-Cell - immunology; Signal Transduction - drug effects; Signal Transduction - immunology; T-Lymphocytes - drug effects; T-Lymphocytes - enzymology; T-Lymphocytes - immunology; T-Lymphocytes - secretion; Transcription Factors - antagonists & inhibitors; Transcription Factors - biosynthesis
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.162.7.3819

Optimal T cell activation requires two signals, one generated by TCR and another by the CD28 costimulatory receptor. In this study, we investigated the regulation of costimulation-induced mitogen-activated protein kinase (MAPK) activation in primary mouse T cells. In contrast to that reported for human 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-CD28 in murine thymocytes and splenic T cells. However, p38 MAPK is activated strongly and synergistically by either CD3/CD28 coligation or PMA/Ca2+ ionophore stimulation, which mimics TCR-CD3/CD28-mediated signaling. Activation of p38 MAPK correlates closely with the stimulation of T cell proliferation. 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 and 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 integration during costimulation of primary mouse T cells, 2) may be involved in the induction of c-Jun activation and augmentation of AP-1 transcriptional activity, and 3) regulates whether T cells enter a state of functional unresponsiveness.