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

Nature Immunology volume 10, pages 10181025 (2009) | Download Citation

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Abstract

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 α and β-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 α- and β-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.

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Acknowledgements

We thank T. Adachi (Tokyo Medical and Dental University), V. Horejsi (Charles University), L. Nitschke (Friedrich-Alexander-University Erlangen, Germany), M. Reth (Max-Planck-Institute of Immunobiology), B. Schraven (Otto-von-Guericke-University) and E. Vigorito (Babraham Institute) for reagents; W. Schuh and H.M. Jäck for assistance with retroviral transduction of primary B cells; and H. Scherer for cell sorting. Supported by the Deutsche Forschungsgemeinschaft (FOR 521), the European Community (PADnet) and the Medical Faculty of Göttingen University.

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Affiliations

  1. Institute of Cellular and Molecular Immunology, Faculty of Medicine, Georg-August-University Göttingen, Göttingen, Germany.

    • Niklas Engels
    • , Lars Morten König
    • , Christina Heemann
    • , Johannes Lutz
    • , Sebastian Griep
    • , Verena Schrader
    •  & Jürgen Wienands
  2. Laboratory of Immunology, Graduate School of Biomedical Science, Tokyo Medical and Dental University, Tokyo, Japan.

    • Takeshi Tsubata

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Contributions

N.E. designed, did and supervised experiments and wrote the paper; L.M.K. designed and did experiments; C.H., J.L., S.G. and V.S. did experiments; T.T. provided essential reagents; and J.W. supervised the project and wrote the paper.

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Correspondence to Jürgen Wienands.

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DOI

https://doi.org/10.1038/ni.1764

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