The Journal of Experimental Medicine
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Published online 3 July 2006 doi:10.1084/jem.20060221
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 7, 1785-1794
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ARTICLE

 Igß tyrosine residues contribute to the control of B cell receptor signaling by regulating receptor internalization

Anna Gazumyan1,2, Amy Reichlin3, and Michel C. Nussenzweig1,2

1 Laboratory of Molecular Immunology and 2 Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10021
3 Department of Pediatrics, Division of Neonatology, New York University Medical School, New York, NY 10016

CORRESPONDENCE Anna Gazumyan: gazumya{at}mail.rockefeller.edu

Immunoglobulin (Ig){alpha} and Igß initiate B cell receptor (BCR) signaling through immune receptor tyrosine activation motifs (ITAMs) that are targets of SH2 domain–containing kinases. To examine the function of Igß ITAM tyrosine resides in mature B cells in vivo, we exchanged these residues for alanine by gene targeting (IgßAA). Mutant mice showed normal development of all B cell subtypes with the exception of B1 cells that were reduced by fivefold. However, primary B cells purified from IgßAA mice showed significantly decreased steady-state and ligand-mediated BCR internalization and higher levels of cell surface IgM and IgD. BCR cross-linking resulted in decreased Src and Syk activation but paradoxically enhanced and prolonged BCR signaling, as measured by cellular tyrosine phosphorylation, Ca++ flux, AKT, and ERK activation. In addition, B cells with the ITAM mutant receptor showed an enhanced response to a T-independent antigen. Thus, Igß ITAM tyrosines help set BCR signaling threshold by regulating receptor internalization.

Abbreviations used: BCR, B cell receptor; CGG, chicken {gamma} globulin; ITAM, immune receptor tyrosine activation motif; MAPK, mitogen-activated protein kinase; NP, 4-hydroxy-3-nitrophenylacetyl; PLC-{gamma}2, phospholipase C-{gamma}2; SHIP, SH2-containing inositol polyphosphate 5-phosphatase; SHP-1, SH2-containing tyrosine phosphatase 1.


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