The Journal of Experimental Medicine
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Published 26 November 2001. doi:10.1084/jem.194.11.1583
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© Rockefeller University Press, 0022-1007/2001/12/1583/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 11, December 3, 2001 1583-1596

Original Article

 Ligand-independent Signaling Functions for the B Lymphocyte Antigen Receptor and Their Role in Positive Selection during B Lymphopoiesis

Gregory Bannish1, Ezequiel M. Fuentes-Pananá1, John C. Cambier2, Warren S. Pear1 and John G. Monroe1

1 University of Pennsylvania School of Medicine, Department of Pathology and Laboratory Medicine, Philadelphia, PA 19104
2 Department of Immunology, University of Colorado Health Science Center and National Jewish Medical and Research Center, Denver, CO 80206

Address correspondence to John G. Monroe, University of Pennsylvania School of Medicine, Rm. 311 BRBII, 421 Curie Blvd., Philadelphia, PA 19104. Phone: 215-898-2873; Fax: 215-573-2014; E-mail: monroej{at}mail.med.upenn.edu

Signal transduction through the B cell antigen receptor (BCR) is determined by a balance of positive and negative regulators. This balance is shifted by aggregation that results from binding to extracellular ligand. Aggregation of the BCR is necessary for eliciting negative selection or activation by BCR-expressing B cells. However, ligand-independent signaling through intermediate and mature forms of the BCR has been postulated to regulate B cell development and peripheral homeostasis. To address the importance of ligand-independent BCR signaling functions and their regulation during B cell development, we have designed a model that allows us to isolate the basal signaling functions of immunoglobulin (Ig){alpha}/Igß-containing BCR complexes from those that are dependent upon ligand-mediated aggregation. In vivo, we find that basal signaling is sufficient to facilitate pro-B -> pre-B cell transition and to generate immature/mature peripheral B cells. The ability to generate basal signals and to drive developmental progression were both dependent on plasma membrane association of Ig{alpha}/Igß complexes and intact immunoregulatory tyrosine activation motifs (ITAM), thereby establishing a correlation between these processes. We believe that these studies are the first to directly demonstrate biologically relevant basal signaling through the BCR where the ability to interact with both conventional as well as nonconventional extracellular ligands is eliminated.

Key Words: B lymphocytes • pre-B cell receptor • B cell development • B cell antigen receptor • signal transduction


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