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 CD21−CD27−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 ofPlasmodium falciparum(Pf)–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 ofPf- and HA-specific atBCs that did not differ proportionally from atBCs within the total B cell population. BCR sequencing identified clonal relationships betweenPf-specific atBCs, activated B cells (actBCs), and classical memory B cells (MBCs) and revealed comparable degrees of somatic hypermutation. At the healthy baseline,Pf-specific atBCs were transcriptionally distinct fromPf-specific actBCs and classical MBCs. In response to acute febrile malaria,Pf-specific atBCs and actBCs up-regulated similar intracellular signaling cascades.Pf-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 (TFH) cells. In the presence of TFHcells 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.