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.
Highlights
The vigorous response of IgG-switched memory B cells to recurring pathogens involves enhanced signalling from their B-cell antigen receptors (BCRs)
Phosphorylation of SLP65 by activated Spleen tyrosine kinase (Syk) allows the formation of a multimolecular protein complex consisting of the key enzymes for BCR-induced Ca2 þ mobilization, the protein tyrosine kinases (PTKs) Bruton’s tyrosine kinase (Btk) and phospholipase C-g2 (PLC-g2), both of which bind to phospho-SLP65 via their SH2 domains[15,16]
The integrity of the Ca2 þ pathway in the transfectants was verified through stimulation of their endogenous membrane-bound IgM (mIgM)-BCRs (Fig. 1f). These results show that the immunoglobulin tail tyrosine (ITT) is the principal signal amplification device of memory-type BCRs in higher vertebrates
Summary
The vigorous response of IgG-switched memory B cells to recurring pathogens involves enhanced signalling from their B-cell antigen receptors (BCRs). Phosphorylation of SLP65 by activated Syk allows the formation of a multimolecular protein complex consisting of the key enzymes for BCR-induced Ca2 þ mobilization, the PTK Bruton’s tyrosine kinase (Btk) and phospholipase C-g2 (PLC-g2), both of which bind to phospho-SLP65 via their SH2 domains[15,16]. The formation of this complex is critical for activation of PLC-g2 by Btk and subsequent generation of the second messengers diacylglycerol and inositol-1,4,5-trisphosphate (IP3) by cleavage of the membrane lipid phosphatidylinositol-4,5-bisphosphate. Experiments using genetically modified mice demonstrated that the cytoplasmic tail of mIgG1 a γ 1m Human γ 1m Mouse γ 2am Mouse γ 1m Camel γ 1m Cow γ 1m Dog γ 1m Pig γ 3m Dolphin γ 1m Platypus εm Human εm Mouse εm Platypus υm Duck υm Anolis υ2m Alligator b wt 4xA YA
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