An abrupt and concordant initiation of apoptosis: antigen-dependent death of CD8+ CTL.
The ability of CD8+ cytotoxic T lymphocytes (CTL) to clear viral infections may be limited when high avidity CTL encounter supra-optimal antigen density on antigen-presenting cells (APC) and undergo antigen-dependent apoptosis of CTL (ADAC). Previously, we have shown ADAC in CD8+ populations to be Fas independent, TNF-alpha receptor 2 (TNFR2) mediated, caspase dependent, and accompanied by a decrease in Bcl-2. We now employ flow cytometry to follow ADAC within individual CD8+ cells to demonstrate that the intense TCR signal induced in high avidity CTL by supra-optimal antigen density results 8 - 16 h later in a caspase-independent TNFR2 down-modulation that is directly related to the stimulating APC antigen density and concludes in a rapid onset of apoptosis by 18 - 24 h. Individual CTL undergoing apoptosis exhibit a dramatic and concurrent: (1) positive staining with Annexin V and propidium iodide; (2) transformation to a smaller cell size characteristic of apoptosis; and (3) a nearly complete loss of Bcl-2, c-IAP1, and TRAF2. We conclude that the antigen-dependent apoptosis of CD8+ CTL occurs when a tandem TCR/TNFR2 signal initiates an abrupt and concordant onset of multiple apoptotic events.
Derby
M A
MA
Molecular Immunogenetics and Vaccine Research Section, Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1578, USA.
Snyder
J T
JT
Tse
R
R
Alexander-Miller
M A
MA
Berzofsky
J A
JA
D000818:Animals; D017304:Annexin A5 / Q000032:analysis; D000941:Antigens / Q000276:immunology*; D015703:Antigens, CD / Q000502:physiology; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D061945:Caspase Inhibitors; D020169:Caspases / Q000502:physiology; D015536:Down-Regulation; D051379:Mice; D008807:Mice, Inbred BALB C; D011506:Proteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D047889:Receptors, Tumor Necrosis Factor, Type II; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D017304:Annexin A5; D000941:Antigens; D015703:Antigens, CD; D061945:Caspase Inhibitors; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D020169:Caspases