Recruitment of the cytoplasmic adaptor Grb2 to surface IgG and IgE provides antigen receptor-intrinsic costimulation to class-switched B cells

Nat Immunol. 2009 Sep;10(9):1018-25. doi: 10.1038/ni.1764. Epub 2009 Aug 9.


The improved antibody responses of class-switched memory B cells depend on enhanced signaling from their B cell antigen receptors (BCRs). However, BCRs on both naive and antigen-experienced B cells use the canonical immunoglobulin-associated alpha and beta-protein signaling subunits. Here we identified a BCR isotype-specific signal-amplification mechanism. Whereas immunoglobulin M (IgM)-containing BCRs initiated intracellular signals exclusively through immunoglobulin-associated alpha- and beta-proteins, IgG- and IgE-containing BCRs also used a conserved tyrosine residue in the cytoplasmic segments of immunoglobulin heavy chains. When phosphorylated, this tyrosine recruited the adaptor Grb2, resulting in sustained protein kinase activation and prolonged generation of second messengers, which together culminated in enhanced B cell proliferation. Hence, membrane-bound IgG and IgE exert antigen recognition as well as costimulatory functions, thereby rendering memory B cells less dependent on T cell help.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology*
  • Calcium / metabolism
  • Cell Line, Tumor
  • Cytoplasm / metabolism
  • GRB2 Adaptor Protein / physiology*
  • Humans
  • Immunoglobulin Class Switching*
  • Immunoglobulin E / physiology*
  • Immunoglobulin G / physiology*
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation
  • Protein Transport
  • Receptors, Antigen, B-Cell / physiology*
  • Signal Transduction
  • Tyrosine / metabolism


  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • Grb2 protein, mouse
  • Immunoglobulin G
  • Receptors, Antigen, B-Cell
  • Immunoglobulin E
  • Tyrosine
  • Calcium