Encoding immunological memory in the initiation of B-cell receptor signaling

Abstract

In one of the earliest events in the initiation of antigen-driven antibody responses, naïve, IgM-, and IgD-expressing B cells enter germinal centers where they irreversibly isotype switch to the expression of predominately IgG B-cell receptors (BCRs). The IgG-expressing B cells then undergo rounds of antigen-driven selection, ultimately exiting germinal centers as IgG-expressing memory B cells or plasma blast. This early switch from IgM to IgG begs the question: Of what advantage to the memory response is the B cell's expression of an IgG BCR? Despite convincing evidence that the expression of IgG BCRs is essential for antibody memory responses in vivo, the molecular basis of this requirement is only incompletely understood. Here we describe intrinsic features of IgG BCRs that endow memory B cells with the ability to rapidly and efficiently initiate signaling. Remarkably, efficient signaling is mediated through the cytoplasmic tail of the membrane IgG that binds to synapse associated protein 97, a member of a large family of proteins that are best studied for their role in regulating receptor signaling in neuronal synapses. These findings underscore an interesting parallel in the mechanisms at play in encoding immunological memory and memory in the nervous system.

Figure 1

A view of the early events in the initiation of IgG BCR signaling. From top right: BCRs exist on the B cell surface primarily as monomers in a dimerization incompetent form. Binding to monovalent Ag on the surface of an APC forces the BCR into a dimerization competent form such that when two Ag-engaged BCRs randomly bump they dimerize. Dimers cluster and alter the local lipid environment recruiting Lyn to phosphorylate ITAMs in the IgG BCR tails. BCR clusters continue to grow and the resulting concentration of SSVV motif-containing mIgG tails facilitates binding to SAP97 through its PDZ domains that stabilize the IgG BCR clusters allowing robust signaling.

Figure 2

An alignment of the cytoplasmic tails of mIgs. Shown are alignments of the Ig tail sequences available in NCBI. The SSVV motifs are highlighted in yellow and the ITT motifs in blue.