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

Abstract 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.