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Rapid Induction of Apoptosis in CD8⁺ HIV-1 Envelope-Specific Murine CTLs by Short Exposure to Antigenic Peptide¹

Megumi Takahashi^*, Eiichi Osono^*, Yohko Nakagawa^*, Jian Wang, Jay A. Berzofsky, David H. Margulies and Hidemi Takahashi^2,*

^* Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan; and Molecular Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Disease, and Molecular Immunogenetics and Vaccine Research Section, Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

During primary viral infection, in vivo exposure to high doses of virus causes a loss of Ag-specific CD8⁺ T cells. This phenomenon, termed clonal exhaustion, and other mechanisms by which CTLs are deleted are poorly understood. Here we show evidence for a novel form of cell death in which recently stimulated CD8⁺ HIV-1 envelope gp160-specific murine CTLs become apoptotic in vitro after brief exposure to free antigenic peptide (P18-I10). Peak apoptosis occurred within 3 h of treatment with peptide, and the level of apoptosis was dependent on both the time after initial stimulation with target cells and the number of targets. Using T cell-specific H-2D^d/P18-I10 tetramers, we observed that the apoptosis was induced by such complexes. Induction of apoptosis was blocked by cyclosporin A, a caspase 3 inhibitor, and a mitogen-activated protein kinase inhibitor, but not by Abs to either Fas ligand or to TNF-. Thus, these observations suggest the existence of a Fas- or TNF--independent pathway initiated by TCR signaling that is involved in the rapid induction of CTL apoptosis. Such a pathway may prove important in the mechanism by which virus-specific CTLs are deleted in the presence of high viral burdens.

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