Extracellular vesicles from antigen-activated B cells stimulate oncogenic herpesvirus lytic gene expression

B cell-derived extracellular vesicles (B-EVs) have been associated with immunomodulatory functions like antigen presentation, cytokine signaling, and T cell activation. However, little is known about the general composition of B-EVs or how the state of the donor cells affects the B-EV composition or functions. We performed integrated proteomic, lipidomic, and transcriptomic analyses of EVs secreted by B cells in resting conditions or upon 30 min of B cell receptor (BCR) activation. Antigen-driven BCR stimulation led to acute remodeling of the protein and lipid composition, and RNA cargo of the B-EVs, which also translated into differential responses in recipient B cells. Remarkably, EVs from activated B cells stimulated lytic gene expression of latent oncogenic {gamma}-herpesviruses Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV). These findings suggest a novel mechanism for the potentially oncogenic reactivation of these lifelong-persisting latent herpesviruses, residing in B cells. Our results support a mechanism in which, upon immune activation, B-EVs from antigen-specific B cells induce viral reactivation in bystander B cells in a paracrine manner, providing molecular insights that bridge immune activation and the pathogenesis of {gamma}-herpesvirus infections.