Reactivation of IgG-switched memory B cells by BCR-intrinsic signal amplification promotes IgG antibody production

Abstract

Secondary antibody responses are marked by faster kinetics, improved antibody affinity and a switch from IgM to other immunoglobulin isotypes, most notably IgG, compared with primary responses. These changes protect from reinfection and represent the principle of most vaccination strategies. Yet, the molecular mechanisms that underlie B-cell memory responses are unclear. Here we show, by inactivating the immunoglobulin tail tyrosine (ITT) signalling motif of membrane-bound IgG1 in the mouse, that the ITT facilitates maintenance and reactivation of IgG-switched memory B cells in vivo. The ITT motif equips IgG-switched cells with enhanced BCR signalling capacity, which supports their competitiveness in secondary immune reactions and drives the formation of IgG-secreting plasma cells even in the absence of T-cell help. Our results demonstrate that ITT signalling promotes the vigorous production of IgG antibodies and thus provide a molecular basis for humoral immunological memory.

Antibody repertoire and gene expression dynamics of diverse human B cell states during affinity maturation

“…Perhaps underpinning this, unswitched MBCs also expressed higher levels of the transcription factor genes POU2F2 (OCT2) and FOXP1 than class-switched MBCs (Figure 5F), which coordinate the capacity of B cells to respond normally to antigen receptor signals and directly repress key regulators of plasma cell differentiation respectively (van Keimpema et al, 2015, Corcoran et al, 2014). This is consistent with switched IgG + MBCs being more likely to differentiate into plasma cells, while unswitched IgM + MBCs are more likely to re-enter or form secondary GC responses to gain higher affinity (Dogan et al, 2009, Lutz et al, 2015, Seifert et al, 2015). Indeed, we found that unswitched preGC MBCs exhibited significantly higher expression of many genes linked with the preGC state, including those associated with class switch recombination of their antibody genes (Figure 5G-H).…”

“…In particular, we noted elevated expression in unswitched MBCs of genes known to regulate B cell migration within lymphoid tissues and genes with the potential to signal to and activate other immune cell types, including IL6, CLEC2B, CR2 (CD21), CKLF, S1PR1, CCR6 , and SEMA7A (Figure 5F; Arkatkar et al, 2017, Suzuki et al, 2008, Elgueta et al, 2015, Cinamon et al, 2004, Han et al, 2001, Welte et al, 2006). This could all contribute to the increased capacity of IgM + MBCs to re-initiate GC reactions as part of a recall memory response (Dogan et al, 2009, Lutz et al, 2015, Seifert et al, 2015).…”

An autoimmune disease variant of IgG1 modulates B cell activation and differentiation

“…It remains unclear how autoreactive IgG + B cells are maintained in a quiescent state under physiological immune homeostasis and how these checkpoints are broken in pathological conditions. IgG-B cell receptor (IgG-BCR) potently enhances memory IgG antibody responses via the evolutionarily conserved cytoplasmic tail of membrane-bound IgG (mIgG-tail) (5)(6)(7)(8)(9)(10). The mIgG-tail amplifies BCR signaling via its phospho-immunoglobulin tail tyrosine (ITT) motif, which recruits the adaptor protein Grb2 to enhance Ca 2+ mobilization, synergistically with Bruton's tyrosine kinase (Btk) and phospholipase C-g2 (PLC-g2) (5,11).…”

Control of memory B cell responses by extrinsic and intrinsic mechanisms

“…To test whether the BCR-intrinsic signal amplification through the ITT is truly B cell autonomous, purified ITT-mutant and wild type IgG1 memory B cells were adoptively transferred into RAG-negative recipient mice, and challenged in the absence of T cells. The difference between the recall abilities of wild type and ITT-mutant IgG1 memory B cells was as striking as in the presence of T cells34 . The same result was obtained when Grb2-negative and Grb2-positive IgG memory B cells were compared in the same assay33 , showing that not only the ITT itself but also its downstream signaling pathway is required to lower the activation threshold of the IgG memory B cell compartment and thereby favor IgG-production in secondary antibody responses under competitive conditions.…”

“…The biological impact of the ITT-mediated BCR signal amplification circuit was demonstrated by the dramatically impaired memory response of an ITT-mutant mouse expressing an IgG1-BCR with an ITT-to-phenylalanine (YF) exchange 34 …”