Inhibition of Fas‐mediated apoptosis by the B cell antigen receptor through c‐FLIP

Cross‐linking of the B cell antigen receptor (BCR) induces resistance to Fas (APO‐1 / CD95)‐dependent apoptosis and thereby regulates one mechanism of B cell selection during antigen stimulation. To investigate the molecular mechanism by which BCR signaling regulates the Fas pathway, we examined the expression of constituents of the death‐inducing signaling complex (DISC), including Fas, FADD, caspase‐8 and cellular FLICE‐inhibitory protein (c‐FLIP). No significant changes in the cellular levels of Fas, FADD or caspase‐8 were observed after BCR cross‐linking. By contrast, the long isoform of c‐FLIP (c‐FLIPL) was significantly up‐regulated by BCR cross‐linking in primary B cells and in two B cell lines, A20 and WEHI‐279. Moreover, transfection of c‐FLIPL into A20 cells inhibited Fas‐dependent apoptosis and suppressed recruitment of caspase‐8 to the DISC. BCR cross‐linking or FLIP overexpression also protects B cells from TRAIL‐induced apoptosis. Thus, BCR signaling up‐regulates c‐FLIPL and suppresses the Fas‐ and TRAIL‐receptor apoptosis pathways which could be important for tolerance and selection of antigen‐specific B cells.