FLICE-inhibitory protein is a key regulator of germinal center B cell apoptosis

Affinity maturation of the B cell response to antigen (Ag) takes place in t he germinal centers (GCs) of secondary follicles. Two sequential molecular mechanisms underpin this process. First, the B cell repertoire is diversifi ed through hypermutation of the immunoglobulin (Ig) variable region genes. Second, mutant B cell clones with improved affinity for Ag are positively s elected by Ag and CD40 Ligand (L). This selection step is contingent upon " priming" of GC B cells for apoptosis. The molecular means by which B cell a poptosis is initiated and controled in the GC remains unclear. Here, we sho w that GC B cell apoptosis is preceded by the rapid activation of caspase-8 at the level of CD95 death-inducing signaling complex (DISC). We found tha t GC B cells ex vivo display a preformed inactive DISC containing Fas-assoc iated death domain-containing protein (FADD), procaspase-8, and the long is oform of cellular FADD-like IL-1 beta -converting enzyme-inhibitory protein (c-FLIPL) but not the CD95L. In culture, c-FLIPL is rapidly lost from the CD95 DISC unless GC B cells are exposed to the survival signal provided by CD40L. Our results suggest that (a) the death receptor signaling pathway is involved in the affinity maturation of antibodies, and (b) c-FLIPL plays a n active role in positive selection of B cells in the GC.