Membrane sequestration of the mlgG cytoplasmic domain confers a safety trigger mechanism governing the enhanced activation of isotype-switched IgG-B cell receptor

Abstract A hallmark of the adaptive immunity is the memory for previously experienced pathogens. Memory B cells that express the isotype-switched IgG-BCR are in charge of the establishment of the memory IgG antibody response. A trigger safety mechanism is necessary to govern the burst-enhanced activation of a smoking-gun-like IgG-BCR to avoid illegitimate activation. Here, we reported that the specific interaction between positively-charged mIgG cytoplasmic tail (mIgG-tail) and negatively-charged acidic phospholipids of the plasma membrane can sequester the key tyrosine in ITT motif in the membrane hydrophobic core, which help quench mIgG-tail basal level signaling in quiescent B cells. Indeed, we observed that disruption of the interaction in quiescent B cells induced higher basal level phosphorylation of mIgG-tail ITT motif and promoted the survival signal of primary B cell in vivo. Disruption of the interaction also led to excessive recruitment of prominent BCR signaling microclusters into the B cell immunological synapse, more aggressive Ca2+ mobilization and gene expression indicated by Nur77-GFP reporter mice, which ultimately led to hyper-proliferation of primary B cells after antigen engagement. Physiologically, mIgG-tail was released by antigen engagement or Ca2+ mobilization in the initiation of IgG+ B cell activation, which then enhances Ca2+ mobilization, and in turn facilitates more release of mIgG-tail to further enhance memory B cell activation through such a positive feedback mechanism. Conclusively, our findings shed new light on a novel regulatory mechanism of IgG+ memory B cell to balance immunoprotection and immunopathology and provide new perspective of self-tolerance in class-switched IgG+ memory B cells.