J. Exp. Med., Volume 188, Number 8, October 19, 1998 1391-1399

Supraoptimal Peptide-Major Histocompatibility Complex Causes a Decrease in Bcl-2 Levels and Allows Tumor Necrosis Factor  Receptor II-mediated Apoptosis of Cytotoxic T Lymphocytes

By Martha A. Alexander-Miller,^* Michael A. Derby,^* Apurva Sarin, Pierre A. Henkart, and Jay A. Berzofsky^*

From the ^* Molecular Immunogenetics and Vaccine Research Section, Metabolism Branch; and the  Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892

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)--mediated apoptosis resulting from stimulation with supraoptimal peptide-major histocompatibility complex. Here, we show that although death is mediated by TNF- and its receptor (TNF-RII), surprisingly neither the antigen dose dependence of TNF- 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 Bcl-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- by decreasing Bcl-2 levels.

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