A noncomitogenic CD2R monoclonal antibody induces apoptosis of activated T cells by a CD95/CD95-L-dependent pathway.
Clonal expansion of activated T and B cells is controlled by homeostatic mechanisms resulting in apoptosis of a large proportion of activated cells, mostly through interaction between CD95 (Fas or Apo-1) receptor and its ligand CD95-L. CD2, which is considered as a CD3/TCR alternative pathway of T cell activation, may trigger activation-induced cell death, but the role of CD95/CD95-L interaction in CD2-mediated apoptosis remains controversial. We show here that the CD2R mAb YTH 655.5, which does not induce comitogenic signals when associated with another CD2 mAb, triggers CD95-L expression by preactivated but not resting T cells, resulting in CD95/CD95-L-mediated apoptosis. The critical role of CD95/CD95-L interaction was supported by complete inhibition in the presence of the antagonist CD95 mAb ZB4 and by blocking CD95-L synthesis and surface expression by cycloheximide, cyclosporin A, EGTA, or cytochalasin B. YTH 655.5 was shown to stimulate p56lck phosphorylation and enzymatic activity. However, p56lck activation is not sufficient to trigger apoptosis, because other CD2R and CD4 mAbs that activate p56lck do not induce apoptosis. In conclusion, CD2 can mediate nonmitogenic signals, resulting in CD95-L expression and apoptosis of CD95+ cells.
Fournel
S
S
Laboratory of Immunology, Institut National de la Santé et de la Recherche Médicale Unit 80 Claude Bernard University, Hôpital E. Herriot, Lyon, France.
Robinet
E
E
Bonnefoy-Bérard
N
N
Assossou
O
O
Flacher
M
M
Waldmann
H
H
Bismuth
G
G
Revillard
J P
JP
D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D018801:CD2 Antigens / Q000276:immunology*; D002478:Cells, Cultured; D053222:Fas Ligand Protein; D006801:Humans; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D019014:fas Receptor / Q000276:immunology*
D000911:Antibodies, Monoclonal; D018801:CD2 Antigens; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019014:fas Receptor