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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

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.

Key Words: T lymphocytes, cytotoxic • apoptosis • protooncogene • proteins c-bel-2 • tumor necrosis factor

Martha A. Alexander-Miller's current address is Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1064.

Abbreviations used: AICD, activation-induced cell death; BD-FMK, Boc-Asp-fluoromethyl ketone; βZFA-FMK, CBZ-Phe-Ala-fluoromethyl ketone; TRAF, TNF receptor–associated factor.

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