The Journal of Experimental Medicine
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Published online 25 September 2000.
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© The Rockefeller University Press, 0022-1007/2000/10/953/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 7, October 2, 2000 953-964


Original Article

Attenuation of Apoptosis Underlies B Lymphocyte Stimulator Enhancement of Humoral Immune Response

Richard K.G. Doa,c, Eunice Hatadaa, Hayyoung Leea, Michelle R. Tourignya, David Hilbertd, and Selina Chen-Kianga,b
a Department of Pathology, Weill Medical College of Cornell University, New York, New York 10021
b Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10021
c Cornell–Rockefeller University–Sloan-Kettering Institute Tri-Institutional MD/PhD Program, Weill Medical College of Cornell University, New York, New York 10021
d Human Genome Sciences, Rockville, Maryland 20850

Correspondence to: Selina Chen-Kiang, Department of Pathology, Weill Medical College of Cornell University, 1300 York Ave., C-338, New York, NY 10021. Tel:212-746-6440 Fax:212-746-8302

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-{kappa}B 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.

Key Words: primary B cell, CD40, nuclear factor {kappa}B, Bcl-2, autoimmunity


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