Co-receptor (CD4/CD8) engagement enhances CD3-induced apoptosis in thymocytes. Implications for negative selection.
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 p56lck, 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.
McConkey
D J
DJ
Department of Cell Biology, M.D. Anderson Cancer Center, Houston, TX 77030.
Fosdick
L
L
D'Adamio
L
L
Jondal
M
M
Orrenius
S
S
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology*; D016827:CD8 Antigens / Q000276:immunology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D011505:Protein-Tyrosine Kinases / Q000276:immunology; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology
D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D011505:Protein-Tyrosine Kinases; D002118:Calcium