B lymphocytes that enter the germinal center late preferentially differentiate into memory cells that recognize subdominant epitopes.

Germinal center (GC) responses are initially seeded by founder B cells and subsequently diversified by continual entry of naive B cells that compete for antigen and T cell help. Here, we examined the contribution of these later-arriving invaders to the development of plasma cells (PCs) and memory B cells (MBCs). We developed a dual-recombinase reporter approach that enabled pre- and post-GC B cell lineage tracing upon vaccination or infection. After immunization with haptenated antigen, a combination tetanus and diphtheria vaccine (Tenivac), or SARS-CoV-2, fate-mapped invaders preferentially gave rise to MBCs as opposed to PCs. Antibodies expressed by invader-derived MBCs harbored fewer somatic mutations, exhibited lower affinity, and bound to subdominant antigenic epitopes relative to founder MBCs. Invader-derived MBCs also contributed to repertoire diversification after infection with murine-adapted influenza A. Our findings indicate that invader GC B cells are an important source of humoral immune memory diversification after vaccination or infection.