Ligation of Major Histocompatability Complex (MHC) Class I Molecules on Human T Cells Induces Cell Death through PI-3 Kinase–induced c-Jun NH2-terminal Kinase Activity: A Novel Apoptotic Pathway Distinct from Fas-induced Apoptosis

• DOI: 10.1083/jcb.139.6.1523
• Publication Date: 2002-07-26T16:47:50Z
• Authors: Søren Skov; Pia Klausen; Mogens H. Claesson
• Keywords: Cell Nucleus; Mitogen-Activated Protein Kinase Kinases; Cytoplasm; MAP Kinase Kinase 4; Recombinant Fusion Proteins; Histocompatibility Antigens Class I; JNK Mitogen-Activated Protein Kinases; Apoptosis; DNA Fragmentation; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Antibodies; Androstadienes; Jurkat Cells; Microscopy, Electron; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; 0302 clinical medicine; Heterochromatin; Calcium-Calmodulin-Dependent Protein Kinases; Humans; Mitogen-Activated Protein Kinases

Ligation of major histocompatability complex class I (MHC-I) molecules expressed on T cells leads to both growth arrest and apoptosis. The aim of the current study was to investigate the intracellular signal pathways that mediate these effects. MHC-I ligation of human Jurkat T cells induced a morphologically distinct form of apoptosis within 6 h. A specific caspase inhibitor, which inhibited Fas-induced apoptosis, did not affect apoptosis induced by MHC-I ligation. Furthermore, MHC-I–induced apoptosis did not involve cleavage and activation of the poly(ADP- ribose) polymerase (PARP) endonuclease or degradation of genomic DNA into the typical fragmentation ladder, both prominent events of Fas-induced apoptosis. These results suggest that MHC-I ligation of Jurkat T cells induce apoptosis through a signal pathway distinct from the Fas molecule. In our search for other signal pathways leading to apoptosis, we found that the regulatory 85-kD subunit of the phosphoinositide-3 kinase (PI-3) kinase was tyrosine phosphorylated after ligation of MHC-I and the PI-3 kinase inhibitor wortmannin selectively blocked MHC-I–, but not Fas-induced, apoptosis. As the c-Jun NH2-terminal kinase (JNK) can be activated by PI-3 kinase activity, and has been shown to be involved in apoptosis of lymphocytes, we examined JNK activation after MHC-I ligation. Strong JNK activity was observed after MHC-I ligation and the activity was completely blocked by wortmannin. Inhibition of JNK activity, by transfecting cells with a dominant-negative JNKK– MKK4 construct, led to a strong reduction of apoptosis after MHC-I ligation. These results suggest a critical engagement of PI-3 kinase–induced JNK activity in apoptosis induced by MHC-I ligation.