No receptor stands alone: IgG B-cell receptor intrinsic and extrinsic mechanisms contribute to antibody memory

Abstract

Acquired immunological memory is a striking phenomenon. A lethal epidemic sweeps through a naïve population, many die but those who survive are never "attacked twice - never at least fatally", as the historian Thucydides observed in 430 BCE. Antibody memory is critical for protection against many human infectious diseases and is the basis for nearly all current human vaccines. Antibody memory is encoded, in part, in isotype-switched immunoglobulin (Ig)G-expressing memory B cells that are generated in the primary response to antigen and give rise to rapid, high-affinity and high-titered antibody responses upon challenge with the same antigen. How IgG-B-cell receptors (BCRs) and antigen-induced IgG-BCR signaling contribute to memory antibody responses are not fully understood. In this review, we summarize exciting new advances that are revealing the cellular and molecular mechanisms at play in antibody memory and discuss how studies using different experimental approaches will help elucidate the complex phenomenon of B-cell memory.

Figure 1

Schematic presentation of IgM-BCRs and IgG-BCRs. (A) IgM-BCRs composed of membrane-bound forms of IgM (light blue indicates the light chain, dark blue indicates the heavy chain) associated with a heterodimer of Igα and Igβ (green) on a mature naïve B cell. The mIg and the Igα/Igβ heterodimer are associated through non-covalent interactions. (B) IgG-BCRs composed of membrane-bound forms of IgG (light pink indicates the light chain, dark pink indicates the heavy chain) associated with the Igα/Igβ heterodimer (green) on a memory B cell. In A and B, the BCRs are depicted in compartmentalized plasma membrane regions that are maintained by membrane-proximal actin fence and anchored transmembrane protein pickets as proposed by Kusumi et al.^,,. The ITAM-containing cytoplasmic tails of Igα/Igβ heterodimer within the IgM- or IgG-BCR complexes are also shown.

Figure 2

An alignment of the cytoplasmic tails of mIgs. Shown are alignments of the mIg tail sequences from different species that are available in NCBI. The SSVV motifs are highlighted in yellow and the ITT motifs in pink color.

Figure 3

A contemporary view of antigen-binding-induced activation of BCR signaling pathways. A highly simplified version of the view of BCR signaling pathways is given. Early biochemical studies indicated that PTKs from three different families, including Lyn, Syk and Btk, are activated following BCR and antigen recognition, forming the typical membrane-proximal signalosome. Such signalosome complex is further stabilized by the involvement of a series of adaptor proteins including BLNK and GRB2. Upon the recruitment of PI3K and PLCγ2 to these membrane-proximal signalosome complexes, these two signaling molecules are activated, the former leading to the production of PIP₃ from PIP₂, while the latter resulting in the production of IP₃ and DAG from PIP₂. Starting from this point, BCR signaling gets quite diverse and triggers at least four different downstream signaling cascades^,, toward the transcriptional activation or regulation of NF-κB, NF-AT, FoxO and MAPK pathways.

Figure 4

A simplified summary of IgG-BCR-intrinsic and -extrinsic factors that work together to enhance the activation and differentiation of memory B cells. Most of the IgG-BCR-intrinsic and -extrinsic factors discussed in this review are depicted in this cartoon to show their potential location and interacting proteins in enhancing the activation and differentiation of IgG-BCR-expressing memory B cells, but not IgM-BCR-expressing mature naïve B cells. IgG-BCR-intrinsic factors likely involve the adaptor protein Grb2 recruited through the membrane distal ITT motif and the scaffolding protein SAP97 recruited through the membrane-proximal SSVV motif of mIgG cytoplasmic tail. These IgG-BCR-intrinsic factors may be responsible for the enhanced calcium responses through some unidentified mechanisms. IgG-BCR-extrinsic factors likely involve the transcription factor Bach2, the expression of which is repressed in IgG-BCR-expressing memory B cells but not in IgM-BCR-expressing mature naïve B cells. The repression of Bach2 in memory B cells is required for enhanced plasma cell differentiation of these cells.