High affinity IgM+ memory B cells are generated through a germinal center-dependent pathway

•Germinal center reaction in spleen.•Active induction of somatic hypermutation in IgM.•Down-regulation of class-switch recombination.

During a T cell-dependent immune response, B cells undergo clonal expansion and selection and the induction of isotype switching and somatic hypermutation (SHM). Although somatically mutated IgM+ memory B cells have been reported, it has not been established whether they are really high affinity B cells. We tracked (4-hydroxy-3-nitrophenyl) acetyl hapten-specific GC B cells from normal immunized mice based on affinity of their B cell receptor (BCR) and performed BCR sequence analysis. SHM was evident by day 7 postimmunization and increased with time, such that high affinity IgM+ as well as IgG+ memory B cells continued to be generated up to day 42. In contrast, class-switch recombination (CSR) was almost completed by day 7 and then the ratio of IgG1+/IgM+ GC B cells remained unchanged. Together these findings suggest that IgM+ B cells undergo SHM in the GC to generate high affinity IgM+ memory cells and that this process continues even after CSR is accomplished.

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