Longitudinal analysis of FcRL5 expression and clonal relationships among classical and atypical memory B cells following malaria

Chronic and frequently recurring infectious diseases, such as malaria, are associated with expanded populations of atypical memory B cells (MBCs). These cells are different from classical MBCs by the lack of surface markers CD21 and CD27 and increased expression of inhibitory receptors, such as FcRL5. While the phenotype and conditions leading to neogenesis of atypical MBCs in malaria-experienced individuals have been studied extensively, the origin of these cells remains equivocal. Functional similarities between FcRL5 atypical MBCs and FcRL5 classical MBCs have been reported, suggesting that these cells may be developmentally related. Here, a longitudinal analysis of FcRL5 expression in various B cell subsets was performed in two children from a high transmission region in Uganda over a 6-month period in which both children experienced a malaria episode. Using B-cell receptor (BCR)-sequencing to track clonally related cells, the connections between IgM and IgG atypical MBCs and other B cell subsets were studied. The highest expression of FcRL5 was found among IgG atypical MBCs, but FcRL5 cells were present in all MBC subsets. Following malaria, FcRL5 expression increased in all IgM MBC subsets analysed here: classical, activated, and atypical MBCs, while results for IgG MBC subsets were inconclusive. IgM atypical MBCs showed few connections with other B cell subsets, higher turnover than IgG atypical MBCs, and were predominantly derived from naïve B cells and FcRL5 IgM classical MBCs. In contrast, IgG atypical MBCs were clonally expanded and connected with classical MBCs. IgG atypical MBCs present after a malaria episode mainly originated from FcRL5 IgG classical MBCs. Collectively, these results suggest fundamental differences between unswitched and class-switched B cell populations and provide clues about the primary developmental pathways of atypical MBCs in malaria-experienced individuals.