The Journal of Experimental Medicine
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Published online April 9, 2007
doi:10.1084/jem.20061923
The Journal of Experimental Medicine, Vol. 204, No. 4, 759-769
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Horikawa et al.
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ARTICLE

 Enhancement and suppression of signaling by the conserved tail of IgG memory–type B cell antigen receptors

Keisuke Horikawa1,3, Stephen W. Martin1, Sarah L. Pogue4, Karlee Silver1, Kaiman Peng2, Kiyoshi Takatsu3, and Christopher C. Goodnow1

1 Immunogenomics Laboratory, The Australian Phenomics Facility and 2 Biomolecular Resource Facility, The John Curtin School of Medical Research, The Australian National University, Canberra 0200, Australia
3 Division of Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
4 Medarex, Inc., Milpitas, CA 95035

CORRESPONDENCE Christopher C. Goodnow: Chris.Goodnow{at}anu.edu.au

Immunological memory is characterized by heightened immunoglobulin (Ig) G antibody production caused in part by enhanced plasma cell formation conferred by conserved transmembrane and cytoplasmic segments in isotype-switched IgG B cell receptors. We tested the hypothesis that the IgG tail enhances intracellular B cell antigen receptor (BCR) signaling responses to antigen by analyzing B cells from Ig transgenic mice with IgM receptors or chimeric IgMG receptors containing the IgG tail segment. The IgG tail segment enhanced intracellular calcium responses but not tyrosine or extracellular signal–related kinase (ERK) phosphorylation. Biochemical analysis and crosses to CD22-deficient mice established that IgG tail enhancement of calcium and antibody responses, as well as marginal zone B cell formation, was not due to diminished CD22 phosphorylation or inhibitory function. Microarray profiling showed no evidence for enhanced signaling by the IgG tail for calcium/calcineurin, ERK, or nuclear factor {kappa}B response genes and little evidence for any enhanced gene induction. Instead, almost half of the antigen-induced gene response in IgM B cells was diminished 50–90% by the IgG tail segment. These findings suggest a novel "less-is-more" hypothesis to explain how switching to IgG enhances B cell memory responses, whereby decreased BCR signaling to genes that oppose marginal zone and plasma cell differentiation enhances the formation of these key cell types.

Abbreviations used: BCR, B cell antigen receptor; ERK, extracellular signal–related kinase; HEL, hen egg lysozyme; ITAM, immunoreceptor tyrosine–based activation motif; MAP, mitogen-activated protein; MEK, MAP kinase/ERK kinase; SHP-1, Src homology domain 2–containing protein tyrosine phosphatase.


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