Co-receptor (CD4/CD8) engagement enhances CD3-induced apoptosis in thymocytes. Implications for negative selection
McConkey, D.J.; Fosdick, L.; D'Adamio, L.; Jondal, M.; Orrenius, S.
Journal of Immunology 153(6): 2436-2443
1994
ISSN/ISBN: 0022-1767 PMID: 8077659 Document Number: 432219
Negative selection of self-reactive immature T cells is mediated by TCR engagement and is thought to occur via apoptosis (programmed cell death). The requirement for the co-receptors CD4 and CD8 in negative selection has been demonstrated, but the biochemical mechanisms underlying their involvement in this process remain undefined. Here we present evidence that co-receptor engagement dramatically enhances CD3-induced endonuclease activation and cell death characteristic of apoptosis in immature thymocytes. The responses are associated with increased tyrosine phosphorylation of a number of cellular substrates, including the gamma isoform of phospholipase C, and with increased association of tyrosine phosphoproteins, including the protein tyrosine kinase p56-lck, with the TCR complex. Co-receptor engagement also potentiated CD3-mediated Ca-2+ increases via a mechanism dependent upon tyrosine kinase activation. Sustained Ca-2+ availability was found to be necessary for endonuclease activation and apoptosis to occur. We suggest that CD4 and CD8 may participate in negative selection by enhancing TCR/CD3-induced tyrosine kinase activation and sustained Ca-2+ increases that lead to endonuclease activation and apoptosis in self-reactive CD4+CD8+ thymocytes.