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 homeostat ic mechanisms resulting in apoptosis of a large proportion of activate d cells, mostly through interaction between CD95 (Fas or Apo-1) recept or and its ligand CD95-L, CD2, which is considered as a CD3/TCR altern ative pathway of T cell activation, may trigger activation-induced cel l death, but the role of CD95/CD95-L interaction in CD2-mediated apopt osis 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 th e presence of the antagonist CD95 mAb ZB4 and by blocking CD95-L synth esis and surface expression by cycloheximide, cyclosporin A, EGTA, or cytochalasin B, YTH 655.5 was shown to stimulate p56(lck) phosphorylat ion and enzymatic activity, However, p56(lck) activation is not suffic ient to trigger apoptosis, because other CD2R and CD4 mAbs that activa te p56(lck) do not induce apoptosis. In conclusion, CD2 can mediate no nmitogenic signals, resulting in CD95-L expression and apoptosis of CD 95(+) cells.