HLA CLASS-II SIGNALING MEDIATES CELLULAR ACTIVATION AND PROGRAMMED CELL-DEATH

The class II human leucocyte antigens (HLA class II) are principally p eptide presentation molecules. Signal transduction by these molecules has also been shown to transmit activation signals in both B and T lym phocytes by a pathway including protein tyrosine kinase activation, an intracellular calcium flux, and both the activation and transcription al regulation of protein kinase C (PKC) isoforms. Apoptosis can also r esult from human leukocyte antigen class II stimulation. Inhibitors of gene transcription were used to inhibit activation and, therefore, to distinguish the signal transduction pathways important for apoptosis. This approach provided evidence that cellular activation and apoptosi s undertook separate signaling pathways, and that PKC and intracellula r calcium were shared between the two pathways, while tyrosine kinase activity was essential for cell activation. Further studies using cord blood B cells showed that these cells were incapable of generating a calcium flux after HLA class II ligation and were not subject to cell death. The importance of sustained levels of calcium for programmed ce ll death (PCD) was underlined since the restoration of a calcium flux enabled PCD of cord blood B cells via HLA class II. These results demo nstrate that HLA class II stimulation initiates two distinct signal tr ansduction pathways.