Rapid induction of apoptosis in CD8+ HIV-1 envelope-specific murine CTLs by short exposure to antigenic peptide.
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-alpha. Thus, these observations suggest the existence of a Fas- or TNF-alpha-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.
Takahashi
Megumi
M
Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan.
Osono
Eiichi
E
Nakagawa
Yohko
Y
Wang
Jian
J
Berzofsky
Jay A
JA
Margulies
David H
DH
Takahashi
Hidemi
H
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D019703:Calcineurin / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D005260:Female; D015488:HIV Antigens / Q000008:administration & dosage* / Q000235:genetics; D019302:HIV Envelope Protein gp160 / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism
D015488:HIV Antigens; D019302:HIV Envelope Protein gp160; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D020928:Mitogen-Activated Protein Kinases; D019703:Calcineurin; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases