Activation sensitizes human memory B cells to B-cell receptor-induced apoptosis

The outcome of antigen receptor (B-cell receptor; BCR) ligation on B-cell survival can be influenced by multiple parameters. They are linked to the physical properties of the antigen itself, the maturational stage of the cells and the costimuli provided by different components of the innate and acquired immunity. Here we report that apoptosis prevails over stimulation when a BCR agonist is applied to human memory B cells which have been preactivated by CD40 ligand or anti-immunoglobulin antibodies. The susceptibility of activated memory B cells to BCR-induced killing is correlated with their enhanced expression of the transcripts encoding the pro-apoptotic molecules Bax, c-Myc and p53. The BCR-mediated apoptosis of activated memory B cells does not require extensive cross-linking of the antigen receptors and relies neither on engagement of the FcgammaRII nor on the Fas/Fas ligand (Fas-L) system. Our findings suggest that activation stimuli open the BCR-induced apoptotic pathway in memory B cells. Therefore we propose that the concept of activation-induced cell death (AICD), originally described for T cells, also applies to mature B lymphocytes. The functions fulfilled by the AICD of mature B cells in the regulation of B-cell responses are discussed.