CD62L expression marks SARS-CoV-2 memory B cell subset with preference for neutralizing epitopes

Severe acute respiratory syndrome coronavirus 2-neutralizing antibodies primarily target the spike receptor binding domain (RBD). However, B cell antigen receptors (BCRs) on RBD-binding memory B (B_mem) cells have variation in the neutralizing activities. Here, by combining single B_mem cell profiling with antibody functional assessment, we dissected the phenotype of B_mem cell harboring the potently neutralizing antibodies in coronavirus disease 2019 (COVID-19)-convalescent individuals. The neutralizing subset was marked by an elevated CD62L expression and characterized by distinct epitope preference and usage of convergent V_H (variable region of immunoglobulin heavy chain) genes, accounting for the neutralizing activities. Concordantly, the correlation was observed between neutralizing antibody titers in blood and CD62L⁺ subset, despite the equivalent RBD binding of CD62L⁺ and CD62L^- subset. Furthermore, the kinetics of CD62L⁺ subset differed between the patients who recovered from different COVID-19 severities. Our B_mem cell profiling reveals the unique phenotype of B_mem cell subset that harbors potently neutralizing BCRs, advancing our understanding of humoral protection.