The Journal of Experimental Medicine
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Published online 29 September 2003 doi:10.1084/jem.20030411
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© Rockefeller University Press, 0022-1007/2003/10/1119 $5.00
The Journal of Experimental Medicine, Volume 198, Number 7, 1119-1126

Brief Definitive Report

Loss of the Pro-Apoptotic BH3-only Bcl-2 Family Member Bim Inhibits BCR Stimulation–induced Apoptosis and Deletion of Autoreactive B Cells

Anselm Enders, Philippe Bouillet, Hamsa Puthalakath, Yuekang Xu, David M. Tarlinton and Andreas Strasser

The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia

Address correspondence to Andreas Strasser, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3050, Australia. Phone: 61-3-9345-2555; Fax: 61-3-9347-0852; email: strasser{at}wehi.edu.au; or David M. Tarlinton, 1G Royal Parade, Parkville, VIC 3050, Australia. Phone: 61-3-9345-2555; Fax: 61-3-9347-0852; email: tarlinton{at}wehi.edu.au

During development, the stochastic process assembling the genes encoding antigen receptors invariably generates B and T lymphocytes that can recognize self-antigens. Several mechanisms have evolved to prevent the activation of these cells and the concomitant development of autoimmune disease. One such mechanism is the induction of apoptosis in developing or mature B cells by engagement of the B cell antigen receptor (BCR) in the absence of T cell help. Here we report that B lymphocytes lacking the pro-apoptotic Bcl-2 family member Bim are refractory to apoptosis induced by BCR ligation in vitro. The loss of Bim also inhibited deletion of autoreactive B cells in vivo in two transgenic systems of B cell tolerance. Bim loss prevented deletion of autoreactive B cells induced by soluble self-antigen and promoted accumulation of self-reactive B cells developing in the presence of membrane-bound self-antigen, although their numbers were considerably lower compared with antigen-free mice. Mechanistically, we determined that BCR ligation promoted interaction of Bim with Bcl-2, inhibiting its survival function. These findings demonstrate that Bim is a critical player in BCR-mediated apoptosis and in B lymphocyte deletion.

Key Words: apoptosis • transgenic mice • tolerance • gene knockout • autoimmunity


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