Intercellular epigenomic signaling during B cell maturation

ABSTRACT B cell maturation is crucial for effective adaptive immunity. It requires a complex signaling network to mediate antibody diversification through mutagenesis. B cells also rely on queues from other cells within the germinal center. Recently, a novel class of intercellular signals mediated by extracellular vesicles (EVs) has emerged. Studies have shown B cell EV-mediated signaling is involved in immune response regulation and tumorigenesis. However, the mechanistic role of B cell EVs is not yet established. We herein study the biological properties and physiological function of B cell EVs during B cell maturation. We use emerging technologies to profile B cell EVs surface marker signatures at the single particle level, molecular cargo, and physiological roles in B cell maturation. EV ncRNA cargo, characterized by RNA-seq, identified an EV-mediated novel non-coding RNA regulatory network for B cell maturation. A previously uncharacterized micro-RNA (miR-5099) in combination with a set of long non-coding RNA carried within B cell EVs is shown to be important for antibody diversification. The physiological role of EVs in B cell maturation is investigated using EV blockade assays and complementation studies using diverse EV sources further confirmed the physiological role and mode of action of EVs in B cell maturation.