A Temporal Switch in the Germinal Center Determines Differential Output of Memory B and Plasma Cells

•Long-lived memory B cells are made predominantly in the early germinal center (GC)•Long-lived bone-marrow-resident plasma cells are made very late in the GC response•Subsets of memory B cells are also produced in a temporal order•A substantial fraction of long-lived IgM memory B cells are made prior to GC onset

SummaryThere is little insight into or agreement about the signals that control differentiation of memory B cells (MBCs) and long-lived plasma cells (LLPCs). By performing BrdU pulse-labeling studies, we found that MBC formation preceded the formation of LLPCs in an adoptive transfer immunization system, which allowed for a synchronized Ag-specific response with homogeneous Ag-receptor, yet at natural precursor frequencies. We confirmed these observations in wild-type (WT) mice and extended them with germinal center (GC) disruption experiments and variable region gene sequencing. We thus show that the GC response undergoes a temporal switch in its output as it matures, revealing that the reaction engenders both MBC subsets with different immune effector function and, ultimately, LLPCs at largely separate points in time. These data demonstrate the kinetics of the formation of the cells that provide stable humoral immunity and therefore have implications for autoimmunity, for vaccine development, and for understanding long-term pathogen resistance.