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Article

Julie Lang^*, B. Arnold, G. Hammerling, Alan W. Harris, Stanley Korsmeyer^||, David Russell^*, Andreas Strasser, and David Nemazee^*,¶

From the ^* Division of Basic Sciences, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206; Tumor Immunology Program, German Cancer Research Center, Im Neuenheimer Feld 280, 6900 Heidelberg, Germany; Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050 Australia; ^|| Department of Medicine, Microbiology and Immunology, Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, Missouri 63198; and ^¶ Department of Immunology, University of Colorado Health Sciences Center, Denver, Colorado 80220

The mechanisms that establish immune tolerance in immature and mature B cells appear to be distinct. Membrane-bound autoantigen is thought to induce developmental arrest and receptor editing in immature B cells, whereas mature B cells have shortened lifespans when exposed to the same stimulus. In this study, we used Eµ–bcl-2-22 transgenic (Tg) mice to test the prediction that enforced expression of the Bcl-2 apoptotic inhibitor in B cells would rescue mature, but not immature, B cells from tolerance induction. To monitor tolerance to the natural membrane autoantigen H-2K^b, we bred 3–83µ (anti-K^k,b) Ig Tg mice to H-2^b mice or to mice expressing transgene-driven K^b in the periphery. In 3–83µ/bcl-2 Tg mice, deletion of autoreactive B cells induced by peripheral K^b antigen expression in the liver (MT-K^b Tg) or epithelia (KerIV-K^b Tg), was partly or completely inhibited, respectively. Furthermore, Bcl-2 protected peritoneal B-2 B cells from deletion mediated by acute antigen exposure, but this protection could be overcome by higher antigen dose. In contrast to its ability to block peripheral self-tolerance, Bcl-2 overexpression failed to inhibit central tolerance induced by bone marrow antigen expression, but instead, enhanced the receptor editing process. These studies indicate that apoptosis plays distinct roles in central and peripheral B cell tolerance.

¹ Abbreviations used in this paper: BCR, B cell receptor; BrdU, 5-bromo-2'-deoxyuridine; CD, central deleting; ND, nondeleting; Tg, transgenic.

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