Human memory B cells show plasticity and adopt multiple fates upon recall response to SARS-CoV-2

The B cell response to different pathogens uses tailored effector mechanisms and results in functionally specialized memory B (B(m)) cell subsets, including CD21(+) resting, CD21(–)CD27(+) activated and CD21(–)CD27(–) B(m) cells. The interrelatedness between these B(m) cell subsets remains unknown. Here we showed that single severe acute respiratory syndrome coronavirus 2-specific B(m) cell clones showed plasticity upon antigen rechallenge in previously exposed individuals. CD21(–) B(m) cells were the predominant subsets during acute infection and early after severe acute respiratory syndrome coronavirus 2-specific immunization. At months 6 and 12 post-infection, CD21(+) resting B(m) cells were the major B(m) cell subset in the circulation and were also detected in peripheral lymphoid organs, where they carried tissue residency markers. Tracking of individual B cell clones by B cell receptor sequencing revealed that previously fated B(m) cell clones could redifferentiate upon antigen rechallenge into other B(m) cell subsets, including CD21(–)CD27(–) B(m) cells, demonstrating that single B(m) cell clones can adopt functionally different trajectories.