CD40 stimulation of B-cell chronic lymphocytic leukaemia cells enhances the anti-apoptotic profile, but also Bid expression and cells remain susceptible to autologous cytotoxic T-lymphocyte attack. 
To enhance the poor antigen-presenting capacity of B-cell chronic lymphocytic leukaemia (B-CLL), CD40 triggering has been considered as an active immunotherapy.  However, CD40 stimulation also has an anti-apoptotic effect and may further impair the dysregulated response of B-CLL to apoptotic stimuli.  Therefore, we measured the expression of virtually all regulators of apoptosis before and after CD40 stimulation.  These findings were correlated with sensitivity for chemotherapy- and death-receptor-induced apoptosis and T-cell-mediated killing.  CD40 stimulation enhanced the constitutive anti-apoptotic profile of B-CLL cells by upregulation of Bcl-xL and Bfl-1 and downregulation of the BH3-only protein Harakiri.  Unexpectedly, the BH3-only protein Bid was strongly induced.  Functionally, CD40-stimulated B-CLL cells became resistant to drug-induced apoptosis and, despite upregulation of CD95 and Bid, were not sensitive to CD95L. In contrast, autologous T cell killing, triggered by loading CLL cells with viral (CMV) peptides, was very efficient both before and after CD40 stimulation.  Upon CTL interaction, CLL targets underwent mitochondrial depolarization and caspase-3 activation.  Thus, despite an increased anti-apoptotic profile, CD40 triggered B-CLL cells remain excellent targets for resident cytotoxic T cells.  These data support therapeutic exploitation of CD40 stimulation in B-CLL, provided that a strong CTL component is induced.