CD2-induced apoptosis in activated human peripheral T cells: a Fas-independent pathway that requires early protein tyrosine phosphorylation.
Short-term activated peripheral T lymphocytes are susceptible to apoptotic cell death triggered by CD2 mAbs. The aim of this study was to examine whether the CD2-mediated pathway of apoptosis is linked to the Fas death pathway, as this is the case for CD3/TCR-triggered apoptosis in several models of T cells. Using T lymphocytes from patients harboring Fas gene mutations and displaying a profound defect in Fas signaling of cell death, we show that CD2- (but not CD3-) mediated apoptosis still proceeds normally. In normal activated T cells, CD3-mediated apoptosis is prevented by reagents that block the Fas/Fas-ligand interaction, namely soluble M3 (an antagonistic anti-Fas mAb) and soluble human Fas.Fc, a fusion protein able to bind released Fas-ligand. In contrast, CD2 signaling of apoptosis resists these blocking agents. Neither new protein synthesis nor the activation of calcineurin was required for CD2- and Fas-mediated apoptosis, suggesting that latent cytoplasmic "death" molecules were activated upon stimulation of the cells. In both cases, protein tyrosine kinases were transiently activated, as is exemplified by the autophosphorylation and exokinase activity of p56lck, yielding overlapping yet nonidentical profiles of protein tyrosine phosphorylation. Pretreating the cells with herbimycin A, before the addition of the apoptotic stimuli, almost completely inhibited CD2 transmembrane signaling of apoptosis, but left intact Fas-induced apoptosis. Our data suggest that CD2 is a Fas-independent cell death pathway that might contribute directly to the elimination of T cells expanding during an immune reaction.
Mollereau
B
B
Equipe d'Immunologie Cellulaire et de Transplantation, Villejuif, France.
Deckert
M
M
Déas
O
O
Rieux-Laucat
F
F
Hirsch
F
F
Bernard
A
A
Fischer
A
A
Lynch
D H
DH
Charpentier
B
B
Le Deist
F
F
Senik
A
A
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D018801:CD2 Antigens / Q000494:pharmacology* / Q000502:physiology; D017252:CD3 Complex / Q000502:physiology; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000235:genetics; D008297:Male; D009154:Mutation / Q000276:immunology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D019014:fas Receptor / Q000235:genetics / Q000276:immunology / Q000502:physiology*
D000911:Antibodies, Monoclonal; D018801:CD2 Antigens; D017252:CD3 Complex; D011993:Recombinant Fusion Proteins; D019014:fas Receptor; D011505:Protein-Tyrosine Kinases