Atypical B cells are part of an alternative lineage of B cells that participates in responses to vaccination and infection in humans

The diversity of circulating human B cells is unknown. We use single-cell RNA sequencing (RNA-seq) to examine the diversity of both antigen-specific and total B cells in healthy subjects and malaria-exposed individuals. This reveals two B cell lineages: a classical lineage of activated and resting memory B cells and an alternative lineage, which includes previously described atypical B cells. Although atypical B cells have previously been associated with disease states, the alternative lineage is common in healthy controls, as well as malaria-exposed individuals. We further track Plasmodium-specific B cells after malaria vaccination in naive volunteers. We find that alternative lineage cells are primed after the initial immunization and respond to booster doses. However, alternative lineage cells develop an atypical phenotype with repeated boosts. The data highlight that atypical cells are part of a wider alternative lineage of B cells that are a normal component of healthy immune responses. [Display omitted] •Single-cell RNA-seq reveals two distinct B cell lineages•An alternative lineage contains CXCR3+ and atypical B cells•Alternative B cells are primed after primary vaccination and respond to boosters•Alternative B cells adopt a more atypical phenotype following repeated antigen exposure Using single-cell RNA sequencing, Sutton et al. show that a population of “atypical” B cells, normally associated with disease, are part of a wider landscape of alternative B cells that participate in normal responses to vaccination.