IgD from atypical-like memory B cells and plasma cells targets commensal and environmental antigens

Human tonsils from the nasopharyngeal mucosa mount frontline antibody responses, including IgD secretion by IgD⁺IgM^– plasma cells (IgD-PCs). The developmental origins and functional significance of these IgD responses remain poorly understood. Here, we show that most IgD-PCs clonally emerge from a heterogeneous population of IgD class-switched IgD⁺IgM^– memory (IgD-ME) B cells that reside within the epithelial, subepithelial, and interfollicular areas of the nasopharyngeal mucosa and share transcriptional and phenotypic properties with atypical B cells. These IgD-ME B cells arise from a mutation-intensive pathway that involves integrated innate and adaptive signals and engenders reactivities to respiratory commensal bacteria, common environmental antigens, and allergens. Such reactivities weaken in germline IgD revertants. Thus, the secreted IgD response heavily relies on nasopharyngeal mucosal IgD-ME B cells via a germinal center–imprinted mutational program that presumably enhances mucosal homeostasis and environmental tolerance.