The origin and fate of malaria-associated atypical memory B cells

Abstract

Abstract Chronic and frequently recurring infectious diseases, such as malaria, are commonly associated with expanded populations of atypical memory B cells (atMBCs, here defined as CD19+CD20+CD21−CD27− B cells). While the phenotype and conditions leading to the generation of atMBCs in malaria-experienced individuals have extensively been studied, the origin and fate of these cells remain largely elusive. Using B cell receptor (BCR) sequencing to track clonally related cells present before and after a malaria episode in 5-year-old Ugandan children, we observed that IgM+ atMBCs were predominantly derived from naïve B cells, while IgG+ atMBCs present after a malaria episode mainly originated from FcRL5+IgG+ classical MBCs (cMBCs, CD19+CD20+CD21+CD27+ B cells). IgM+ atMBCs showed fewer connections with other B cell subsets and higher turnover than IgG+ atMBCs. Single-cell transcriptomics analysis revealed that IgG+ atMBCs could be divided into two distinct clusters, one of which was maintained up to 6 months after infection. These results underscore the heterogeneity among atMBCs and highlight differences in their longevity. Finally, we observed that atMBCs from malaria-naïve and malaria-experienced donors showed many similarities in BCR characteristics, such as levels of somatic hypermutation, suggesting that atMBCs undergo similar differentiation pathways in response to different types of pathogens. In terms of BCR characteristics, IgM+ atMBCs of all donors closely resembled NBCs, while IgG+ atMBCs were more similar to IgG+ cMBCs. Collectively, our results highlight differences between unswitched and switched atMBC populations and shed light on the origin and fate of atMBCs in malaria-experienced individuals.