Attenuation of apoptosis underlies B lymphocyte stimulator enhancement of humoral immune response.
B lymphocyte stimulator (BLyS) is a newly identified monocyte-specific TNF family cytokine. It has been implicated in the development of autoimmunity, and functions as a potent costimulator with antiimmunoglobulin M in B cell proliferation in vitro. Here we demonstrate that BLyS prominently enhances the humoral responses to both T cell-independent and T cell-dependent antigens, primarily by attenuation of apoptosis as evidenced by the prolonged survival of antigen-activated B cells in vivo and in vitro. BLyS acts on primary splenic B cells autonomously, and directly cooperates with CD40 ligand (CD40L) in B cell activation in vitro by protecting replicating B cells from apoptosis. Moreover, although BLyS alone cannot activate the cell cycle, it is sufficient to prolong the survival of naive resting B cells in vitro. Attenuation of apoptosis by BLyS correlates with changes in the ratios between Bcl-2 family proteins in favor of cell survival, predominantly by reducing the proapoptotic Bak and increasing its prosurvival partners, Bcl-2 and Bcl-xL. In either resting or CD40L-activated B cells, the NF-kappaB transcription factors RelB and p50 are specifically activated, suggesting that they may mediate BLyS signals for B cell survival. Together, these results provide direct evidence for BLyS enhancement of both T cell-independent and T cell-dependent humoral immune responses, and imply a role for BLyS in the conservation of the B cell repertoire. The ability of BLyS to increase B cell survival indiscriminately, at either a resting or activated state, and to cooperate with CD40L, further suggests that attenuation of apoptosis underlies BLyS enhancement of polyclonal autoimmunity as well as the physiologic humoral immune response.
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Department of Pathology, Weill Medical College of Cornell University, New York, New York 10021, USA.
Hatada
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Lee
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Tourigny
M R
MR
Hilbert
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Chen-Kiang
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D019297:2,4-Dinitrophenol / Q000276:immunology; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D000917:Antibody Formation; D017209:Apoptosis / Q000276:immunology*; D053264:B-Cell Activating Factor; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008565:Membrane Proteins / Q000008:administration & dosage / Q000096:biosynthesis / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000276:immunology; D052002:NF-kappa B p50 Subunit; D009596:Nitrophenols / Q000276:immunology; D010648:Phenylacetates; D022242:Pneumococcal Vaccines / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D012710:Serum Albumin, Bovine / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D051841:Transcription Factor RelB; D014157:Transcription Factors / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000276:immunology*; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; D005719:gamma-Globulins / Q000276:immunology
D000907:Antibodies, Bacterial; D053264:B-Cell Activating Factor; C494772:BAK1 protein, human; C494811:BCL2L1 protein, human; C494773:Bak1 protein, mouse; C494812:Bcl2l1 protein, mouse; D008565:Membrane Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D009596:Nitrophenols; D010648:Phenylacetates; D022242:Pneumococcal Vaccines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C497593:RELB protein, human; C497594:Relb protein, mouse; C505719:TNFSF13B protein, human; C505720:Tnfsf13b protein, mouse; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; D005719:gamma-Globulins; C026242:4-hydroxy-5-nitrophenyl acetic acid; D023201:CD40 Ligand; D051841:Transcription Factor RelB; D012710:Serum Albumin, Bovine; D019297:2,4-Dinitrophenol