Ig beta tyrosine residues contribute to the control of B cell receptor signaling by regulating receptor internalization.
Immunoglobulin (Ig)alpha and Igbeta 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 Igbeta ITAM tyrosine resides in mature B cells in vivo, we exchanged these residues for alanine by gene targeting (Igbeta(AA)). 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 Igbeta(AA) 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, Igbeta ITAM tyrosines help set BCR signaling threshold by regulating receptor internalization.
Gazumyan
Anna
A
Laboratory of Molecular Immunology and 2Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10021, USA. gazumya@mail.rockefeller.edu
Reichlin
Amy
A
Nussenzweig
Michel C
MC
D000409:Alanine / Q000235:genetics; D000818:Animals; D018390:Gene Targeting; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D014443:Tyrosine / Q000235:genetics / Q000502:physiology*
D007136:Immunoglobulins; D011947:Receptors, Antigen, B-Cell; D014443:Tyrosine; D000409:Alanine