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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 1018–1025 (2009)Cite this article

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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Figure 1: The ITT of γ2am is a target of protein kinases.
Figure 2: ITT phosphorylation of γ2am improves the activation of BCR-proximal signal effectors.
Figure 3: Tyrosine phosphorylation of γ2am potentiates Ca2+ mobilization.
Figure 4: ITT phosphorylation distinguishes IgG-BCR from IgM-BCR signaling.
Figure 5: Specific and exclusive association of phospho-γ2am with Grb2.
Figure 6: Grb2 recruitment is critical for the IgG-BCR-induced proliferative burst.
Figure 7: The IgE-BCR uses ITT-mediated signal amplification.
Figure 8: ITT signal amplification relies on BCR integration.

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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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Authors and 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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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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Engels, N., König, L., Heemann, C. et al. Recruitment of the cytoplasmic adaptor Grb2 to surface IgG and IgE provides antigen receptor–intrinsic costimulation to class-switched B cells. Nat Immunol 10, 1018–1025 (2009). https://doi.org/10.1038/ni.1764

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