Cell cycle control of apoptosis in human leukemic T cells.
Eukaryotic cell cycle is regulated by feedback controls that can arrest the progress of the cell cycle at specific checkpoints. Failure of feedback controls may predispose cells to undergo apoptotic death in response to a variety of stimuli. Transformed cell lines often carry defects in one or more proteins that regulate cell cycle, and therefore can be used as a model to study how cell cycle controls cell death. The present study investigated whether TCR/CD3-induced apoptosis of human leukemic T cells is cell cycle dependent. Studies of Jurkat and Sup-T13, two human leukemic T cell lines, demonstrated that anti-CD3 Ab-driven activation results in a transient, reversible inhibition of DNA synthesis in Jurkat cells, but results in a persistent, irreversible inhibition of DNA synthesis in Sup-T13 cells. Anti-CD3 mAb blocked Jurkat cells at the G1/S interface without inducing cell death. In contrast, anti-CD3 mAb allowed Sup-T13 cells to enter S phase but inhibited progression into G2 phase and triggered cell death. Electron microscopy showed that anti-CD3 mAb-stimulated Sup-T13 cells acquired the characteristic morphology of apoptosis. The nuclear DNA appeared as oligonucleosome-sized fragments by gel electrophoresis, and as an apoptotic peak displaying lower fluorescence than the DNA content of cells in G1 phase by DNA flow microfluorometry. DNA fragmentation correlated with entry into S phase. The DNA synthesis inhibitor aphidicolin arrested Sup-T13 cells at the G1/S interface and prevented the apoptosis. Therefore, DNA synthesis is required for executing the apoptosis program initiated by TCR/CD3 stimulation of Sup-T13 cells. These data are consistent with the hypothesis that the suicide of activated cycling T cells upon encountering autoantigens may be one of the mechanisms for the immune system to prevent autoimmunity.
Zhu
L
L
Human Immunogenetics Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98104.
Anasetti
C
C
D017209:Apoptosis / Q000502:physiology*; D015551:Autoimmunity; D002453:Cell Cycle; D004273:DNA, Neoplasm / Q000032:analysis / Q000096:biosynthesis; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology*; D016853:Muromonab-CD3 / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000096:biosynthesis; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000276:immunology*; D016196:S Phase; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D007376:Interleukin-2; D016853:Muromonab-CD3; D009363:Neoplasm Proteins; D017260:Receptor-CD3 Complex, Antigen, T-Cell