LAUSR

Significance Persistent viral infection remains a major source of global morbidity and mortality. Studies using a persistent clone of lymphocytic choriomeningitis virus (LCMV) revealed that in addition to optimal functions and interactions of T and B cells, production of cytokines is essential in promoting long-term control of infection. Here we report that B cells are an indispensable source of IL-27 during persistent LCMV infection. B cell–derived IL-27 promotes viral control via supporting accumulations of virus-specific CD8 and CD4 T cells. During later stages of infection, B cell–derived IL-27 promotes production of IFN-γ and IL-21 by virus-specific CD4 T and Tfh cells, respectively. Our study unveils the critical role of a B cell–secreted cytokine in controlling a persistent infection. Recent studies have identified a critical role for B cell–produced cytokines in regulating both humoral and cellular immunity. Here, we show that B cells are an essential source of interleukin-27 (IL-27) during persistent lymphocytic choriomeningitis virus (LCMV) clone 13 (Cl-13) infection. By using conditional knockout mouse models with specific IL-27p28 deletion in B cells, we observed that B cell–derived IL-27 promotes survival of virus-specific CD4 T cells and supports functions of T follicular helper (Tfh) cells. Mechanistically, B cell–derived IL-27 promotes CD4 T cell function, antibody class switch, and the ability to control persistent LCMV infection. Deletion of IL-27ra in T cells demonstrated that T cell–intrinsic IL-27R signaling is essential for viral control, optimal CD4 T cell responses, and antibody class switch during persistent LCMV infection. Collectively, our findings identify a cellular mechanism whereby B cell–derived IL-27 drives antiviral immunity and antibody responses through IL-27 signaling on T cells to promote control of LCMV Cl-13 infection.