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Most vaccines induce robust antibody and memory B-cell (MBC) responses that are capable of mediating protective immunity. However, antibody titers wane following vaccination necessitating the administration of booster vaccines to maintain a protective antibody titer. MBCs are stably maintained following vaccination and can rapidly give rise to antibody-secreting cells or undergo further affinity maturation upon antigen re-encounter. Repeated antigen encounter results in the development of MBCs that encode antibodies capable of mediating broadly protective immunity against viruses such as SARS-CoV-2 and influenza. Here, we summarize emerging evidence that MBCs are a heterogeneous population composed of transcriptionally and phenotypically distinct subsets that have discrete roles in mediating protective immunity upon antigen re-encounter and examine the implications of these findings for the development of vaccines capable of eliciting broadly protective immunity.

Introduction

Memory B cells (MBCs) are long-lived cells that can rapidly differentiate into antibody-secreting cells or undergo further affinity maturation upon antigen re-encounter 1, 2, 3, 4. MBCs can arise through either a germinal center (GC)-dependent or -independent pathway with GC-independent MBCs contributing to protective immunity against pathogens such as Ehrlichia muris and malaria 5, 6, 7, 8, 9. However, GC-independent MBCs do not undergo affinity maturation and are generally not class-switched, limiting their ability to protect against some viral infections 5, 8, 10. The GC is a structure that forms in the center of the follicle following vaccination or infection in which B cells compete for a limiting amount of T-cell-derived signals that are necessary for their continued proliferation, somatic hypermutation (SHM), and eventual differentiation into MBCs or long-lived plasma cells (LLPCs) [11]. Vaccine-induced MBCs that encode antibodies capable of neutralizing SARS-CoV-2 variants generally display high levels of SHM and are likely a product of the GC response 12, 13.

Section snippetsRegulation of memory B-cell development

GC B-cell differentiation is regulated based on signals received through CD40 and the B-cell receptor (BCR) (Figure 1) [11]. High-affinity GC B cells will preferentially bind antigen via the BCR and interact with cognate CD40L-expressing T cells present in the light zone. GC B cells that receive strong T-cell help differentiate into plasma cells, while cells that receive intermediate T-cell help migrate to the dark zone where they will undergo additional proliferation and SHM. GC B cells that

Kinetics of memory B-cell development in mice and humans

Pulse-labeling experiments in mice have shown that there is a temporal switch in GC B-cell differentiation with MBCs arising before LLPCs (Figure 2a) [34]. These results are consistent with other studies in which GC-fate mapping mice were used to show that MBCs tend to arise during the early phases of the GC response 16, 31•. The mechanisms underlying the temporal switch in GC output are currently unclear. It has been hypothesized that decreasing antigen availability and subsequent T-cell help

Spatial heterogeneity in the memory B-cell response

MBC localization regulates their capacity to encounter antigen and become reactivated upon re-infection. MBCs residing in the LN can either exit the tissue to traffic to other sites or migrate to the subcapsular sinus (SCS), where they can interact with antigen-bearing SCS macrophages before migrating back into the follicle (Figure 3a) [49]. The SCS is an important site of MBC reactivation [50]. MBCs are distributed between the follicle and marginal zone in the spleen in mice (Figure 3b) 51, 52

Phenotypic heterogeneity in the memory B-cell response

The MBC response is composed of transcriptionally and phenotypically distinct subsets. Early work proposed that functionally distinct MBC subsets are defined based on isotype expression, with IgM+ MBCs re-entering the GC and class-switched MBCs differentiating into antibody-secreting cells upon antigen re-encounter 1, 3. This model was refined by the finding that expression of the cell surface receptors CD80 and PDL2 defines functionally distinct MBC subsets, with CD80+ PDL2+ MBCs

Implications for vaccine design

We propose that MBC subsets arise at different stages of the immune response with the phenotype of these subsets regulating their fate and ability to encode protective antibodies upon pathogen re-encounter. MBC subsets that are GC-independent or arise early in GC response may be sufficient to protect against pathogens, such as flaviviruses, in which germline-encoded MBCs can respond following heterologous challenge [36]. However, heterosubtypic protection against viruses such as SARS-CoV-2 or

Author contributions

The authors contributed equally to all aspects of the article.

Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

The Laidlaw laboratory is supported by National Institute of Allergy and Infectious Diseases (NIAID, USA) grants DP2AI169978 and K22AI153015. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the NIAID or NIH. Figures created using Biorender.

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