Atypical B cells up-regulate costimulatory molecules during malaria and secrete antibodies with T follicular helper cell support.

Several infectious and autoimmune diseases are associated with an expansion of CD21CD27 atypical B cells (atBCs) that up-regulate inhibitory receptors and exhibit altered B cell receptor (BCR) signaling. The function of atBCs remains unclear, and few studies have investigated the biology of pathogen-specific atBCs during acute infection. Here, we performed longitudinal flow cytometry analyses and RNA sequencing of ()-specific B cells isolated from study participants before and shortly after febrile malaria, with simultaneous analysis of influenza hemagglutinin (HA)-specific B cells as a comparator. At the healthy baseline before the malaria season, individuals had similar frequencies of - and HA-specific atBCs that did not differ proportionally from atBCs within the total B cell population. BCR sequencing identified clonal relationships between -specific atBCs, activated B cells (actBCs), and classical memory B cells (MBCs) and revealed comparable degrees of somatic hypermutation. At the healthy baseline, -specific atBCs were transcriptionally distinct from -specific actBCs and classical MBCs. In response to acute febrile malaria, -specific atBCs and actBCs up-regulated similar intracellular signaling cascades. -specific atBCs showed activation of pathways involved in differentiation into antibody-secreting cells and up-regulation of molecules that mediate B-T cell interactions, suggesting that atBCs respond to T follicular helper (T) cells. In the presence of T cells and staphylococcal enterotoxin B, atBCs of malaria-exposed individuals differentiated into CD38 antibody-secreting cells in vitro, suggesting that atBCs may actively contribute to humoral immunity to infectious pathogens.