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) cell subsets, including CD21 resting, CD21CD27 activated and CD21CD27 B cells. The interrelatedness between these B cell subsets remains unknown. Here we showed that single severe acute respiratory syndrome coronavirus 2-specific B cell clones showed plasticity upon antigen rechallenge in previously exposed individuals. CD21 B 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 cells were the major B 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 cell clones could redifferentiate upon antigen rechallenge into other B cell subsets, including CD21CD27 B cells, demonstrating that single B cell clones can adopt functionally different trajectories.