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

Br J Haematol. 2004 Nov;127(4):404-15. doi: 10.1111/j.1365-2141.2004.05225.x.


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.

MeSH terms

  • Apoptosis / immunology*
  • BH3 Interacting Domain Death Agonist Protein
  • Blotting, Western
  • CD40 Antigens / immunology*
  • Carrier Proteins / metabolism
  • Caspase 3
  • Caspases / metabolism
  • Cytomegalovirus / immunology
  • Flow Cytometry
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / immunology*
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology
  • T-Lymphocytes, Cytotoxic / immunology*
  • Tumor Cells, Cultured
  • Up-Regulation
  • fas Receptor / immunology


  • BH3 Interacting Domain Death Agonist Protein
  • BID protein, human
  • CD40 Antigens
  • Carrier Proteins
  • fas Receptor
  • CASP3 protein, human
  • Caspase 3
  • Caspases