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Review
. 2018 Dec 18:9:2988.
doi: 10.3389/fimmu.2018.02988. eCollection 2018.

Isotype Specific Assembly of B Cell Antigen Receptors and Synergism With Chemokine Receptor CXCR4

Palash C Maity  1 , Moumita Datta  1 , Antonella Nicolò  1 , Hassan Jumaa  1
Affiliations
Review

Isotype Specific Assembly of B Cell Antigen Receptors and Synergism With Chemokine Receptor CXCR4

Palash C Maity et al. Front Immunol. .

Abstract

Expression of the membrane-bound form of the immunoglobulin (Ig) as part of the antigen receptor is indispensable for both the development and the effector function of B cells. Among five known isotypes, IgM and IgD are the common B cell antigen receptors (BCRs) that are co-expressed in naïve B cells. Despite having identical antigen specificity and being associated with the same signaling heterodimer Igα/Igβ (CD79a/CD79b), IgM and IgD-BCR isotypes functionally differ from each other in the manner of antigen binding, the formation of isolated nanoclusters and in their interaction with co-receptors such as CD19 and CXCR4 on the plasma membrane. With recent developments in experimental techniques, it is now possible to investigate the nanoscale organization of the BCR and better understand early events of BCR engagement. Interestingly, the cytoskeleton network beneath the membrane controls the BCR isotype-specific organization and its interaction with co-receptors. BCR triggering results in reorganization of the cytoskeleton network, which is further modulated by isotype-specific signals from co-receptors. For instance, IgD-BCR is closely associated with CXCR4 on mature B cells and this close proximity allows CXCR4 to employ the BCR machinery as signaling hub. In this review, we discuss the functional specificity and nanocluster assembly of BCR isotypes and the consequences of cross-talk between CXCR4 and IgD-BCR. Furthermore, given the role of BCR and CXCR4 signaling in the development and survival of leukemic B cells, we discuss the consequences of the cross-talk between CXCR4 and the BCR for controlling the growth of transformed B cells.

Keywords: B cell antigen receptor (BCR); B cell malignancies; Chemokine receptor 4 (CXCR4); Cytoskeleton; Nanoclusters.

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Figures

Figure 1
Figure 1
Graphical summary of altered peripheral B cell subsets and immune response in IgM KO and IgD KO animals. Schematic representation of B cell development in WT (left), IgM KO (middle), and IgD KO (right) animals highlighting the defect in preBCR signaling, increased follicular (FO) B cell compartment and decreased B1/ MZ B cell compartment in IgM KO animals. In contrast, follicular (FO) B cell compartment is reduced and B1/ MZ B cell compartment is increased in IgD KO animals. In response to antigen, IgD KO animals show a time delay and decreased serum antibody titer compared to WT animals.
Figure 2
Figure 2
Graphical summary and comparison of antigen-based and anti-BCR Fab fragment-based BCR labeling for dSTORM imaging. Top, schematic representation of IgD-BCR nanoscale organization on resting (left) and activated (right) B cells, demonstrating their equally efficient fluorescent labeled NP-antigen (green) binding in contrast to differential fluorescently labeled anti-IgD Fab fragment (red) binding. The accessible sites for antigen and anti-BCR antibody (anti-IgD Fab fragment) of a NP specific IgD- BCR are highlighted by green and red color, respectively. Bottom, schematic of antigen-based dSTORM imaging compared to Fab fragment-based dSTORM imaging of resting and activated IgD-BCR nanoscale organization, allowing quantification of dissociated BCR units upon activation and non-resolving large clusters of activated BCRs due to increase labeling density, respectively.
Figure 3
Figure 3
Schematic representation of CXCL12 and antigen triggered B cell activation. Left, resting B cell membrane showing IgD and IgM BCR nanoclusters differentially localized in actin dense (gray shaded) and actin poor regions, respectively. IgD BCRs are residing in close proximity to CD19 and CXCR4. Middle, CXCL12 induced signaling in B cells depicting the sequential triggering of local actin remodeling, recruitment of Syk and IgD BCR activation followed by signal spreading toward actin poor domains. Right, antigen mediated BCR signaling, Syk recruitment and actin remodeling leading to massive actin remodeling and B cell activation.
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