LAUSR

Summary Memory B cells (MBCs) and plasma cells (PCs) constitute the two cellular outputs of germinal center (GC) responses that together facilitate long‐term humoral immunity. Although expression of the transcription factor BLIMP‐1 identifies cells undergoing PC differentiation, no such marker exists for cells committed to the MBC lineage. Here, we report that the chemokine receptor CCR6 uniquely marks MBC precursors in both mouse and human GCs. CCR6+ GC B cells were highly enriched within the GC light zone (LZ), were the most quiescent of all GC B cells, exhibited a cell‐surface phenotype and gene expression signature indicative of an MBC transition, and possessed the augmented response characteristics of MBCs. MBC precursors within the GC LZ predominantly possessed a low affinity for antigen but also included cells from within the high‐affinity pool. These data indicate a fundamental dichotomy between the processes that drive MBC and PC differentiation during GC responses. Graphical Abstract Figure. No caption available. HighlightsMemory B cell precursors in mouse and human germinal centers are marked by CCR6Memory B cell precursors localize to the germinal‐center light zoneMemory B cell precursors primarily have a low affinity for antigenMemory B cell precursors have acquired rapid response characteristics &NA; Although memory B cells sustain long‐term humoral immunity, the nature of their precursors within the germinal center has remained elusive. Suan et al. demonstrate that these cells are uniquely identified by CCR6 expression in both mouse and human germinal centers, that they are the most quiescent B cells in these structures, and that they are generated within the light zone. Memory B cell precursors have a primarily low affinity for antigen but also include cells emerging from the high‐affinity compartment.