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Published 15 March 2004. doi:10.1084/jem.20031140
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 6, 855-865
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A B Cell Receptor with Two Ig{alpha} Cytoplasmic Domains Supports Development of Mature But Anergic B Cells

Amy Reichlin1, Anna Gazumyan1, Hitoshi Nagaoka3, Kathrin H. Kirsch4, Manfred Kraus5, Klaus Rajewsky5, and Michel C. Nussenzweig1,2

1 Laboratory of Molecular Immunology, 2 Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10021
3 Department of Medical Chemistry and Molecular Biology, Graduate School of Medicine, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
4 Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118
5 Center for Blood Research, Harvard Medical School, Boston, MA 02115

Address correspondence to Michel C. Nussenzweig, 1230 York Ave., Box 220, New York, NY 10021. Phone: (212) 327-8067; Fax: (212) 327-8370; email: nussen{at}mail.rockefeller.edu

B cell receptor (BCR) signaling is mediated through immunoglobulin (Ig){alpha} and Igß a membrane-bound heterodimer. Ig{alpha} and Igß are redundant in their ability to support early B cell development, but their roles in mature B cells have not been defined. To examine the function of Ig{alpha}–Igß in mature B cells in vivo we exchanged the cytoplasmic domain of Ig{alpha} for the cytoplasmic domain of Igß by gene targeting (Igßc->{alpha}c mice). Igßc->{alpha}c B cells had lower levels of surface IgM and higher levels of BCR internalization than wild-type B cells. The mutant B cells were able to complete all stages of development and were long lived, but failed to differentiate into B1a cells. In addition, Igßc->{alpha}c B cells showed decreased proliferative and Ca2+ responses to BCR stimulation in vitro, and were anergic to T-independent and -dependent antigens in vivo.

Key Words: B cell receptor • immunoglobulin • signal transduction • anergy • B cell development

Abbreviations used in this paper: BCR, B cell receptor; BrdU, bromodeoxyuridine; CFDA,SE, 5-carboxyfluorescein diacetate succinimidyl ester; CGG, chicken gamma globulin; IP, immunoprecipitation; ITAM, immunoreceptor tyrosine activation motif; MIg, membrane Ig; NP, nitrophenol.


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