International Immunology, Vol. 14, No. 9, pp. 973-982,
September 2002
© 2002 Japanese Society for Immunology
Prevention of B cell antigen receptor-induced apoptosis by ligation of CD40 occurs downstream of cell cycle regulation
1 Department of Hematology and 2 Department of Experimental Immunology, Academic Medical Center, PO Box 22660, 1100 DD Amsterdam, The Netherlands 3 Department of Hematology, University Medical Center, 3584 CX Utrecht, The Netherlands 4 Present address: Department of Molecular Biology H8, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
Correspondence to: E. Eldering; E-mail: e.eldering{at}amc.uva.nl
Transmitting editor: E. A. Clark
Cross-linking of the B cell antigen receptor (BCR) on germinal center B cells can induce growth arrest and apoptosis, thereby eliminating potentially autoreactive B cells. Using the Burkitt lymphoma cell line Ramos as a model, we studied the commitment to apoptosis following growth arrest, as well as how triggering of CD40 or addition of tumor necrosis factor (TNF)-
can interfere to block cell death. Both BCR triggering and direct induction of growth arrest by sodium butyrate (n-But) caused hypophosphorylation of the retinoblastoma protein (pRb), followed by apoptosis. Interestingly, although CD40 ligation or TNF- efficiently prevented BCR-induced and n-But-induced apoptosis, these co-stimuli did not inhibit, but rather augmented, growth arrest. Analysis of cell cycle regulators showed that each apoptotic and Th stimulus distinctly affected cyclins or cyclin-dependent kinase inhibitors, indicating that growth arrest can be uncoupled from apoptosis. BCR ligation and growth arrest activated the intrinsic or mitochondrial route of apoptosis. CD40 ligation and TNF- prevented release of cytochrome c and activation of caspase-3, which could not be explained by effects on the expression of Bcl-2, Bcl-xL or Bax. Finally, the onset of BCR-induced apoptosis occurred after 10–12 h and addition of CD40 mAb or TNF- at that point still prevented further execution of apoptosis. We conclude that in mature B cells apoptosis is not an obligatory event following growth arrest. Instead, commitment to apoptosis can be rapidly controlled by T cells via CD40 ligand and TNF-, downstream of the pRb-regulated restriction point of the cell cycle, but prior to mitochondrial cytochrome c release.
Keywords: B lymphocytes, CD40, cell cycle, cell death, T–B cell collaboration
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