Abstract
B cells that express the isotype-switched IgG-B cell receptor (IgG-BCR) are one of the driving forces for antibody memory. To allow for a rapid memory IgG antibody response, IgG-BCR evolved into a highly effective signalling machine. Here, we report that the positively charged cytoplasmic domain of mIgG (mIgG-tail) specifically interacts with negatively charged acidic phospholipids. The key immunoglobulin tail tyrosine (ITT) in mIgG-tail is thus sequestered in the membrane hydrophobic core in quiescent B cells. Pre-disruption of such interaction leads to excessive recruitment of BCRs and inflated BCR signalling upon antigen stimulation, resulting in hyperproliferation of primary B cells. Physiologically, membrane-sequestered mIgG-tail can be released by antigen engagement or Ca2+ mobilization in the initiation of B cell activation. Our studies suggest a novel regulatory mechanism for how dynamic association of mIgG-tail with acidic phospholipids governs the enhanced activation of IgG-BCR.
Highlights
B cells that express the isotype-switched IgG-B cell receptor (IgG-BCR) are one of the driving forces for antibody memory
An important but understudied question is how IgG-BCR appropriately ensures an ordered signalling hierarchy of utilizing immunoglobulin tail tyrosine (ITT) signalling to amplify immunoreceptor tyrosine activation motifs (ITAMs) signalling in response to antigen stimulation
The switch from a membranesequestered ITT motif in quiescent cells to a solvent-exposed ITT motif in activated cells ensures an ordered signalling hierarchy in the initiation of IgG-BCR activation. This concept is supported by the observation that IgG-BCR with a solvent-exposed mIgG-tail mutant exhibits an excessive recruitment of prominent BCR signalling microclusters into the B cell immunological synapse and more aggressive downstream signalling including inflated Ca2 þ mobilization upon antigen stimulation, which lead to hyper-proliferation of B cells compared with the wild-type (WT) IgG-BCR
Summary
B cells that express the isotype-switched IgG-B cell receptor (IgG-BCR) are one of the driving forces for antibody memory. IgG-BCRs exhibit a dramatically enhanced capability to oligomerize and form microclusters in response to membrane-bound antigens[7,15] All these studies improve our understanding of how IgG-BCR acquires burst-enhanced signalling via its conserved ITT motif within mIgG-tail. The switch from a membranesequestered ITT motif in quiescent cells to a solvent-exposed ITT motif in activated cells ensures an ordered signalling hierarchy in the initiation of IgG-BCR activation This concept is supported by the observation that IgG-BCR with a solvent-exposed mIgG-tail mutant (mIgG-Linker25-tail) exhibits an excessive recruitment of prominent BCR signalling microclusters into the B cell immunological synapse and more aggressive downstream signalling including inflated Ca2 þ mobilization upon antigen stimulation, which lead to hyper-proliferation of B cells compared with the wild-type (WT) IgG-BCR.
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