Memory B cell heterogeneity: Remembrance of things past

Abstract

B cells that persist for long periods of time after antigen encounter exist as either antibody-producing plasma cells (long-lived plasma cells, LLPCs) that reside primarily in the bone marrow or rapidly responsive memory B cells (MBCs) that reside in the spleen and circulation. Although LLPCs are thought to be non-responsive to a secondary infection, MBCs respond to subsequent infection through the production of antibody-secreting cells, formation of new germinal centers (GCs), and repopulation of the memory pool. Dogma suggests that MBCs express class-switched, somatically hypermutated BCRs after undergoing a GC reaction. Yet this narrow view of MBCs has been challenged over the years and it is now well recognized that diverse MBC subsets exist in both rodents and humans. Here, we review current thoughts on the phenotypic and functional characteristics of MBCs, focusing on a population of somatically hypermutated, high affinity IgM⁺ MBCs that are rapidly responsive to a secondary malaria infection.

Keywords: IgM; T-dependent; antibody; germinal center; memory B cells.

Figure 1

Among memory B cell subsets, survival and plasticity are inversely correlated with the integration of activation signals and terminal differentiation. IgD⁺ MBCs persist for long periods of time, yet do not display surface markers associated with T cell interactions including CD73, CD80, and PD‐L2. However, these cells may be able to form secondary germinal centers. Populations of IgM⁺ and IgG⁺ MBCs that express only 1 of these surface markers retain some plasticity. Expression of 2 or more of the surface molecules CD73, CD80, and PD‐L2 is more frequent among IgG⁺ MBC than IgM⁺ MBCs, and cells with this phenotype are more likely to form plasmablasts during secondary responses

Figure 2

Plasmodium‐specific MBCs. Upon primary infection, naïve B cells can differentiate into (A) short lived plasmablasts (PBs) or long‐lived plasma cells (LLPCs) or (B) memory B cells (MBCs). Distinct populations of MBCs include IgM⁺ and IgG⁺ MBCs, which display features of prior T cell interactions including surface expression of CD73, CD80, and PD‐L2 as well as somatic hypermutation. In contrast, IgD⁺ MBCs appear to be GC‐independent, based on lack of CD73, CD80, and PD‐L2 expression. After secondary antigen encounter, IgM⁺ MBCs rapidly respond by forming IgM⁺ and IgG⁺ plasmablasts, and IgG⁺ MBCs form IgG⁺ plasmablasts slightly delayed compared with IgM⁺ MBCs. The function of IgD⁺ MBCs is unclear, but these cells may form secondary germinal centers