CD40 activation does not protect chronic lymphocytic leukemia B cells fromapoptosis induced by cytotoxic T lymphocytes

Cytotoxic T lymphocytes (CTLs) can kill target cells by the granule/exocyto sis pathway or the Fas-mediated apoptosis pathway. The sensitivity of chron ic lymphocytic leukemia (CLL) B cells to CTL-mediated apoptosis before and after CD40 activation was examined. Resting or CD40-activated CLL cells wer e found to be equally sensitive to class I-restricted CTL-mediated killing. Despite expressing CD95, the CD40-activated CLL target cells were found to be resistant to apoptosis induced by CH11, an IgM CD95 monoclonal antibody (mAb), Consistent with this, inhibitors of caspases, which are involved in the Fas-induced apoptotic pathway (eg, N-carbobenzoxy-Val-Ala-Asp fluorome thyl ketone [z-VAD-fmk]), were unable to block destruction of CLL target ce lls by CTL, In addition, preincubation of the effector T cells with the ant i-fas ligand mAb NOK-2 failed to inhibit their subsequent ability to kill C LL target cells. On the other hand, CTL activity was blocked by inhibitors of the granule exocytosis pathway such;ns ethylene-glyco-tetra-acetic acid or concanamycin A. These results indicate that CD40 activation does not imp air the sensitivity of CLL cells to Pas-independent CTL-mediated apoptosis. (C) 2000 by The American Society of Hematology.