The immunoglobulin tail tyrosine motif upgrades memory-type BCRs by incorporating a Grb2-Btk signalling module

Niklas Engels (), Lars M. König, Wiebke Schulze, Daniel Radtke, Kanika Vanshylla, Johannes Lutz, Thomas H. Winkler, Lars Nitschke and Jürgen Wienands ()
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Niklas Engels: Institute of Cellular and Molecular Immunology, Georg-August-University of Göttingen, Medical Faculty
Lars M. König: Institute of Cellular and Molecular Immunology, Georg-August-University of Göttingen, Medical Faculty
Wiebke Schulze: Institute of Cellular and Molecular Immunology, Georg-August-University of Göttingen, Medical Faculty
Daniel Radtke: Chair of Genetics, Friedrich-Alexander-University Erlangen-Nürnberg
Kanika Vanshylla: Institute of Cellular and Molecular Immunology, Georg-August-University of Göttingen, Medical Faculty
Johannes Lutz: Institute of Cellular and Molecular Immunology, Georg-August-University of Göttingen, Medical Faculty
Thomas H. Winkler: Hematopoiesis Unit, Nikolaus-Fiebiger-Center for Molecular Medicine, Friedrich-Alexander-University Erlangen-Nürnberg
Lars Nitschke: Chair of Genetics, Friedrich-Alexander-University Erlangen-Nürnberg
Jürgen Wienands: Institute of Cellular and Molecular Immunology, Georg-August-University of Göttingen, Medical Faculty

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: Abstract The vigorous response of IgG-switched memory B cells to recurring pathogens involves enhanced signalling from their B-cell antigen receptors (BCRs). However, the molecular signal amplification mechanisms of memory-type BCRs remained unclear. Here, we identify the immunoglobulin tail tyrosine (ITT) motif in the cytoplasmic segments of membrane-bound IgGs (mIgGs) as the principle signal amplification device of memory-type BCRs in higher vertebrates and decipher its signalling microanatomy. We show that different families of protein tyrosine kinases act upstream and downstream of the ITT. Spleen tyrosine kinase (Syk) activity is required for ITT phosphorylation followed by recruitment of the adaptor protein Grb2 into the mIgG-BCR signalosome. Grb2 in turn recruits Bruton’s tyrosine kinase (Btk) to amplify BCR-induced Ca2+ mobilization. This molecular interplay of kinases and adaptors increases the antigen sensitivity of memory-type BCRs, which provides a cell-intrinsic trigger mechanism for the rapid reactivation of IgG-switched memory B cells on antigen recall.

Date: 2014
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DOI: 10.1038/ncomms6456

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