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 apopt otic cell death triggered by CD2 mAbs. The aim of this study was to ex amine whether the CD2-mediated pathway of apoptosis is linked to the F as death pathway, as this is the case for CD3/TCR-triggered apoptosis in several models of T cells, Using T lymphocytes from patients harbor ing Eas gene mutations and displaying a profound defect in Fas signali ng of cell death, we show that CD2- (but not CD3-)mediated apoptosis s till proceeds normally, In normal activated T cells, CDS-mediated apop tosis is prevented by reagents that block the Fas/Fas-ligand interacti on, namely soluble M3 (an antagonistic anti-Fas mAb) and soluble human Fas.Fc, a fusion protein able to bind released Fas-ligand, In contras t, CD2 signaling of apoptosis resists these blocking agents. Neither n ew protein synthesis nor the activation of calcineurin was required fo r CD2- and Fas-mediated apoptosis, suggesting that latent cytoplasmic ''death'' molecules were activated upon stimulation of the cells. In b oth cases, protein tyrosine kinases were transiently activated, as is exemplified by the autophosphorylation and exokinase activity of p56(l ck), yielding overlapping yet nonidentical profiles of protein tyrosin e phosphorylation. Pretreating the cells with herbimycin A, before the addition of the apoptotic stimuli, almost completely inhibited CD2 tr ansmembrane signaling of apoptosis, but left intact Fas-induced apopto sis. Our data suggest that CD2 is a Fas-independent cell death pathway that might contribute directly to the elimination of T cells expandin g during an immune reaction.