Supraoptimal peptide-major histocompatibility complex causes a decrease in bc1-2 levels and allows tumor necrosis factor alpha receptor II-mediated apoptosis of cytotoxic T lymphocytes

J Exp Med. 1998 Oct 19;188(8):1391-9. doi: 10.1084/jem.188.8.1391.


Cytotoxic T lymphocytes (CTLs) are primary mediators of viral clearance, but high viral burden can result in deletion of antigen-specific CTLs. We previously reported a potential mechanism for this deletion: tumor necrosis factor (TNF)-alpha-mediated apoptosis resulting from stimulation with supraoptimal peptide-major histocompatibility complex. Here, we show that although death is mediated by TNF-alpha and its receptor (TNF-RII), surprisingly neither the antigen dose dependence of TNF-alpha production nor that of TNF-RII expression can account for the dose dependence of apoptosis. Rather, a previously unrecognized effect of supraoptimal antigen in markedly decreasing levels of the antiapoptotic protein Bc1-2 was discovered and is likely to account for the gain in susceptibility or competence to sustain the death signal through TNF-RII. This decrease requires a signal through the TCR, not just through TNF-RII. Although death mediated by TNF-RII is not as widely studied as that mediated by TNF-RI, we show here that it is also dependent on proteolytic cleavage by caspases and triggered by a brief initial encounter with antigen. These results suggest that determinant density can regulate the immune response by altering the sensitivity of CTLs to the apoptotic effects of TNF-alpha by decreasing Bc1-2 levels.

MeSH terms

  • Animals
  • Antigens / immunology
  • Apoptosis*
  • Caspases / physiology
  • Major Histocompatibility Complex / physiology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred DBA
  • Proto-Oncogene Proteins c-bcl-2 / analysis*
  • Receptors, Tumor Necrosis Factor / physiology*
  • T-Lymphocytes, Cytotoxic / physiology*
  • Tumor Necrosis Factor-alpha / biosynthesis


  • Antigens
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • Caspases