B cell receptor triggering sensitizes human B cells to TRAIL-induced apoptosis

TRAIL is known to cause death in tumor cells, but physiological regulation of its activity remains poorly characterized. We demonstrate that BCR triggering sensitizes transformed centroblast-like BL cells and peripheral blood memory B cells to TRAIL-mediated apoptosis. The sensitization correlated with surface down-regulation and intracellular retention of TRAIL-R4, along with changes in the expression of several Bcl-2 protein family members. Although enhancing FAS-mediated cell death, CD40 activation protected B cells from TRAIL-induced apoptosis. Combination of Ig cross-linking with CD40 ligation did not prevent TRAIL-R4 down-regulation but induced changes in the mitochondria-regulated pathway of apoptosis that are known to be associated with resistance to TRAIL. Human CD5⁺ B cells, presumably stimulated by reactivity to self without immunological help, exhibited very high ex vivo sensitivity to TRAIL. Our results define the first B-lymphocyte-specific physiological signal that increases cellular sensitivity to TRAIL. This may be important for our understanding of TRAIL involvement in the control of B cell responses and aid in designing TRAIL-based therapies for B cell lymphomas.