Immature thymocytes become sensitive to calcium-mediated apoptosis with the onset of CD8, CD4, and the T cell receptor expression: a role for bcl-2?
During intrathymic negative selection by clonal deletion, crosslinking of the T cell receptor (TCR) induces cell death by delivering an apoptotic signal(s) to the nucleus along a calcium-dependent pathway. We investigated the reactivity of early precursor-containing thymocytes to Ca(2+)-induced signals, and discovered a breakpoint in their sensitivity to calcium-mediated cell death (CMCD). CD25+CD8-4- TCR- (triple negative [TN]) thymocytes stimulated with a calcium ionophore maintain their viability and precursor activity. By contrast, their immediate progeny, CD25-CD8lo4loTCR alpha beta lo (triple low [TL]) cells react to calcium elevation by abrogation of precursor activity and apoptotic cell death. This developmental difference is specific for CMCD, since both CD25+TN and CD25-TL cells are susceptible to steroid-induced apoptosis. The presence of bcl-2 mRNA correlates directly to the resistance to CMCD-CD25+ TN cells express it and CD25-TL cells do not. These experiments show that thymocytes become sensitive to Ca(2+)-induced apoptosis as soon as they begin to express molecules that mediate thymic selection, and suggest that a concomitant downregulation of bcl-2 may mediate this phenomenon.
Andjelić
S
S
Immunology Program, Memorial Sloan-Kettering Cancer Center, New York 10021.
Jain
N
N
Nikolić-Zugić
J
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D015704:CD4 Antigens / Q000096:biosynthesis*; D016827:CD8 Antigens / Q000096:biosynthesis*; D002118:Calcium / Q000494:pharmacology*; D002478:Cells, Cultured; D017931:DNA Primers; D005260:Female; D015870:Gene Expression; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D011519:Proto-Oncogenes; D012333:RNA, Messenger / Q000096:biosynthesis; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology*
D015704:CD4 Antigens; D016827:CD8 Antigens; D017931:DNA Primers; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D011505:Protein-Tyrosine Kinases; D002118:Calcium