FCRL5+ Memory B Cells Exhibit Robust Recall Responses

FCRL5+ atypical memory B cells (atMBCs) expand in many chronic human infections, including recurrent malaria, but studies have drawn opposing conclusions about their function. Here, in mice infected with Plasmodium chabaudi, we demonstrate expansion of an antigen-specific FCRL5+ population that is distinct from previously described FCRL5+ innate-like murine subsets. Comparative analyses reveal overlapping phenotypic and transcriptomic signatures between FCRL5+ B cells from Plasmodium-infected mice and atMBCs from Plasmodium-exposed humans. In infected mice, FCRL5 is expressed on the majority of antigen-specific germinal-center-derived memory B cells (MBCs). Upon challenge, FCRL5+ MBCs rapidly give rise to antibody-producing cells expressing additional atypical markers, demonstrating functionality in vivo. Moreover, atypical markers are expressed on antigen-specific MBCs generated by immunization in both mice and humans, indicating that the atypical phenotype is not restricted to chronic settings. This study resolves conflicting interpretations of atMBC function and suggests FCRL5+ B cells as an attractive target for vaccine strategies. [Display omitted] •Antigen-specific FCRL5+ memory B cells (MBCs) expand in Plasmodium-infected mice•Murine FCRL5+ MBCs resemble human atypical MBCs from Plasmodium-exposed humans•FCRL5+ MBCs are mature, long-lived, and respond robustly to in vivo challenge•Antigen-specific FCRL5+ MBCs are generated by immunization in both mice and humans FCRL5+ atypical memory B cells (MBCs) expand in many chronic human diseases. Using tetramers to track rare antigen-specific cells, Kim et al. show that FCRL5+ MBCs are mature, optimally responsive cells that arise not only in response to infection and protein immunization in mice but also to immunization in humans.