Fas-mediated apoptosis of CD4+ and CD8+ T cells from human immunodeficiency virus-infected persons: differential in vitro preventive effect of cytokines and protease antagonists.
Human immunodeficiency syndrome (HIV) infection leads to a progressive loss of T-cell-mediated immunity associated with T-cell apoptosis. We report here that CD4+ and CD8+ T cells from HIV-1-infected persons are sensitive to Fas (CD95/APO-1)-mediated death induced either by an agonistic anti-Fas antibody or by the physiologic soluble Fas ligand, although showing no sensitivity to tumor necrosis factor alpha-induced death. CD4+ and CD8+ T-cell apoptosis induced by Fas ligation was enhanced by inhibitors of protein synthesis and was prevented either by a soluble Fas receptor decoy or an antagonistic anti-Fas antibody. Fas-mediated apoptosis could also be prevented in a CD4+ or CD8+ T-cell-type manner (1) by several protease antagonists, suggesting the involvement of the interleukin-1beta (IL-1beta)-converting enzyme (ICE)-related cysteine protease in CD4+ T-cell death and of both a CPP32-related cysteine protease and a calpain protease in CD8+ T-cell death; and (2) by three cytokines, IL-2, IL-12, and IL-10, that exerted their effects through a mechanism that required de novo protein synthesis. Finally, T-cell receptor (TCR)-induced apoptosis of CD4+ T cells from HIV-infected persons involved a Fas-mediated death process, whereas TCR stimulation of CD8+ T cells led to a different Fas-independent death process. These findings suggest that Fas-mediated T-cell death is involved in acquired immunodeficiency syndrome (AIDS) pathogenesis and that modulation of Fas-mediated signaling may represent a target for new therapeutic strategies aimed at the prevention of CD4+ T-cell death in AIDS.
Estaquier
J
J
Inserm U415, Lille, France.
Tanaka
M
M
Suda
T
T
Nagata
S
S
Golstein
P
P
Ameisen
J C
JC
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000473:pathology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000473:pathology*; D002154:Calpain / Q000502:physiology; D020170:Caspase 1; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases / Q000502:physiology; D053222:Fas Ligand Protein; D015658:HIV Infections / Q000276:immunology / Q000473:pathology*; D015497:HIV-1; D006801:Humans; D008562:Membrane Glycoproteins / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015398:Signal Transduction; D019014:fas Receptor / Q000187:drug effects / Q000502:physiology*
D000911:Antibodies, Monoclonal; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D011480:Protease Inhibitors; D011500:Protein Synthesis Inhibitors; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D019014:fas Receptor; C505407:CASP3 protein, human; D002154:Calpain; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases; D020170:Caspase 1