Credit: S.Bradbrook/NPG

In human peripheral blood there are two main B cell populations: a naive IgM+CD27− population that has unmutated immunoglobulin genes and a class-switched memory IgG+CD27+ population. IgM+CD27+ memory B cells have also been identified, but the generation and immunological function of these cells are poorly understood. Now, Ralf Küppers and colleagues report that human IgM+ memory B cells are more similar to IgG+ memory B cells than to naive B cells. Human IgM+ memory B cells can re-enter germinal centre (GC) reactions upon antigen re-encounter and they can interact with neutrophils in early inflammatory responses in vitro.

To characterize different human B cell subsets, the authors compared the transcriptional expression profiles of IgM+CD27−, IgG+CD27+ and IgM+CD27+ B cells. The two CD27+ memory B cell subsets showed substantial similarities and were clearly different from the naive CD27−B cells. Gene set enrichment analysis identified shared gene signatures that were associated with a memory B cell phenotype, including genes associated with enhanced antigen responsiveness and plasmablast differentiation.

IgM+ memory B cells have chemotactic activity

Next, the authors investigated differences between IgG+ and IgM+ memory B cells; pairwise gene comparisons revealed more than 400 genes with at least a twofold difference in expression between the two B cell subsets. They identified genes encoding key molecules that have specific functions in IgM+ memory B cells, including carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) and CC-chemokine receptor 2 (CCR2). In vitro chemotactic assays with soluble CEACAM8 (sCEACAM8) and CC-chemokine ligand 2 (CCL2) showed that IgM+ memory B cells have chemotactic activity towards both ligands. Furthermore, IgM+ memory B cells differentiated more readily into antibody-secreting cells than IgG+ memory B cells and naive B cells in response to sCEACAM8 stimulation. Thus, by expressing different surface receptors, IgM+ memory B cells can respond to stimulation by specific signals, which can lead to increased migratory capacity and differentiation into antibody-secreting cells.

Interestingly, both sCEACAM8 and CCL2 are known to be secreted by neutrophils in early phases of inflammatory responses and these molecules help to recruit leukocytes. Co-cultures of neutrophils and IgM+ memory B cells showed that activated neutrophils could stimulate IgM+ memory B cells to differentiate and secrete IgM or class switch to IgG2.

Finally, the authors investigated whether human IgM+ and IgG+ memory B cells show a distinct memory response to antigen recall. IgM+ memory B cells showed greater migration towards signals that direct homing to B cell follicles than naive and IgG+ memory B cells, whereas the naive and IgG+ B cell subsets preferentially migrated towards signals that direct plasma cell homing. This result suggests that IgM+ memory B cells can re-enter GC reactions. Indeed, they found that human IgM+ memory B cells upregulated the expression of the GC-associated transcription factor B cell lymphoma 6 (BCL-6), which indicates that IgM+ memory B cells preferentially adopted a pre-GC B cell phenotype. However, following T cell-independent antigen stimulation, IgM+ memory B cells also differentiated into plasma cells, as they adopted plasma cell morphology and downregulated their expression of BTB and CNC homologue 2 (BACH2). By contrast, human IgG+ memory B cells primarily differentiated into plasma cells following re-encounter with either T cell-dependent or T cell-independent antigen.

Together, these results increase our understanding of human peripheral blood IgM+ memory B cells and reveal the unexpected functional plasticity of these cells.