Plasticity of atypical B cell composition and function in response to malaria

Abstract

Abstract Atypical B cells are generated during a normal adaptive immune response, yet the role of these cells in protective immunity is still largely unknown. Here, we used chronic Plasmodium falciparum exposure as a model to gain insight into the function and potential heterogeneity of atypical B cells in the immune response to infection. To this end, we performed single-cell sequencing on circulating B cells from malaria-experienced individuals. Based on distinct gene expression signatures, we identified three novel atypical B cell subsets. Each subset had an effector profile that translated to one of previously proposed roles for atypical B cells: i) quiescent cells ii) antigen-presenting cells or iii) antibody-secreting cell precursors. We identified differentially expressed cell surface markers that allowed us to track each atypical B cell subset by flow cytometry. We observed that the relative abundance of each subset was influenced by the timing of sample collection in relation to infection. Additionally, our analysis revealed an enrichment of CXCR3+ atypical B cells in adults as compared to children, suggesting further heterogeneity in the context of age or chronic antigen stimulation. To explore the contribution of atypical B cells in response to malaria, we used antigen-tetramers to identify parasite-specific cells. All three atypical B cell subsets harbored antigen-specific B cells that decreased in frequency in the absence of exposure, confirming their active and transient role in malaria immunity. Finally, preliminary results suggest that the three subsets differ in their ability to secrete antibodies after stimulation, highlighting the cellular heterogeneity and distinct effector functions of atypical B cells. National Institutes of Health predoctoral fellowship F31AI169993 (RR) National Institutes of Health grant R35GM128938 (FA) National Institutes of Health grant R01AI153425 (EB)