TY - JOUR
T1 - Co-receptor (CD4/CD8) engagement enhances CD3-induced apoptosis in thymocytes
T2 - Implications for negative selection
AU - McConkey, David J.
AU - Fosdick, Lisa
AU - D'Adamio, Luciano
AU - Jondal, Mikael
AU - Orrenius, Sten
PY - 1994/9/15
Y1 - 1994/9/15
N2 - 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 γ 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 Ca2+ increases via a mechanism dependent upon tyrosine kinase activation. Sustained Ca2+ 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 Ca2+ increases that lead to endonuclease activation and apoptosis in self-reactive CD4+CD8+ thymocytes.
AB - 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 γ 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 Ca2+ increases via a mechanism dependent upon tyrosine kinase activation. Sustained Ca2+ 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 Ca2+ increases that lead to endonuclease activation and apoptosis in self-reactive CD4+CD8+ thymocytes.
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M3 - Article
C2 - 8077659
AN - SCOPUS:0028031243
SN - 0022-1767
VL - 153
SP - 2436
EP - 2443
JO - Journal of Immunology
JF - Journal of Immunology
IS - 6
ER -