An abrupt and concordant initiation of apoptosis: antigen-dependent death of CD8+ CTL

Eur J Immunol. 2001 Oct;31(10):2951-9. doi: 10.1002/1521-4141(2001010)31:10<2951::aid-immu2951>;2-q.


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.

MeSH terms

  • Animals
  • Annexin A5 / analysis
  • Antigens / immunology*
  • Antigens, CD / physiology
  • Apoptosis*
  • CD8-Positive T-Lymphocytes / physiology*
  • Caspase Inhibitors
  • Caspases / physiology
  • Down-Regulation
  • Mice
  • Mice, Inbred BALB C
  • Proteins / analysis
  • Proto-Oncogene Proteins c-bcl-2 / analysis
  • Receptors, Antigen, T-Cell / physiology
  • Receptors, Tumor Necrosis Factor / physiology
  • Receptors, Tumor Necrosis Factor, Type II
  • TNF Receptor-Associated Factor 2
  • Tumor Necrosis Factor-alpha / physiology


  • Annexin A5
  • Antigens
  • Antigens, CD
  • Caspase Inhibitors
  • Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Antigen, T-Cell
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type II
  • TNF Receptor-Associated Factor 2
  • Tumor Necrosis Factor-alpha
  • Caspases