Bim regulates B-cell receptor-mediated apoptosis in the presence of CD40 signaling in CD40-pre-activated splenic B cells differentiating into plasma cells.
B-cell receptor (BCR)-mediated apoptosis is critical for B-cell development and homeostasis. CD40 signaling has been shown to protect immature or mature B cells from BCR-mediated apoptosis. In this study, to understand the fate of CD40-pre-activated splenic B cells stimulated by BCR engagement in the presence of CD40 signaling, murine splenic B cells were cultured with anti-Igκ and anti-CD40 antibodies after pre-activation with anti-CD40 antibody. We found that apoptosis was induced in the cultured B cells even in the presence of CD40 signaling during the 3-4 days cultivation. We detected up-regulation of Bim expression followed by Bax activation in this apoptotic process and cessation of the apoptosis in Bim-deficient B cells, indicating that Bim is a key regulator of the BCR-mediated apoptosis in the presence of CD40 signaling in CD40-pre-activated B cells. Importantly, this BCR-mediated apoptosis in CD40-pre-activated B cells was shown to be induced at the initiation of plasma cell differentiation at around the preplasmablast stage, and Bim-deficient B cells cultured under these conditions differentiated into plasma cells. Additionally, transforming growth factor-β was found to protect CD40-pre-activated B cells from BCR-mediated apoptosis in the presence of CD40 signaling. Our identified BCR-mediated apoptosis, which is unpreventable by CD40 signaling, suggests a potential mechanism that regulates the elimination of peripheral B cells, which should be derived from nonspecific T-dependent activation of bystander B cells and continuous stimulation with antigens including self-antigens in the presence of T cell help through CD40.
Laboratory of Molecular and Cellular Biology, Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan.
Yuanyuan
Y
Gao
Hirotaka
H
Kazama
Shin
S
Yonehara
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010950:Plasma Cells / Q000166:cytology* / Q000276:immunology*; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D019013:CD40 Antigens; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011947:Receptors, Antigen, B-Cell