Interleukin-27-producing B cells are critical regulators of immunity during persistent viral infection

Abstract

Abstract B cells regulate immune responses by both generating antibodies and through cell surface interactions and cytokine production that provide signals to various cells to modulate humoral and cell-mediated immunity. During persistent viral infection, IL-27R is required for viral control which correlates with impaired anti-viral CD4+ T cell responses and lower LCMV-specific antibody production. Here, using mice with conditional B cell–specific IL-27 p28 deletion, we identify IL-27-producing B cells as key players in promoting control of persistent viral infection. Mice in which B cells lacked IL-27 p28 expression lost the ability to control persistent LCMV infection. The impaired immunity was associated with the reduction of GC B cells, plasma cells and Tfh cells. In addition, these mice also displayed reduced virus-specific CD8 T cells and lost the ability to expand CXCR5+ follicular CD8 T cells following anti-IFNAR1 treatment, suggesting that B-cell-derived IL-27 p28 regulates immunity by providing signals to T cells. To assess the role of IL-27 signaling in T cells we generated IL-27R conditional KO mice by mating IL-27Ra-floxed mice with CD4 and Granzyme B-Cre strains. Mice in which IL-27Ra was conditionally ablated in all T cells lost the ability to control persistent LCMV infection. In addition, these mice produced significantly lower titers of virus-specific IgG2a throughout the course of infection despite similar levels of virus-specific IgG1. Finally, we identify plasma cells expressing the transcription factor Blimp1 as a major source of IL-27 p28 during persistent LCMV infection. Overall, our study highlights the importance of IL-27-producing B cells in regulating T cell responses and control of persistent viral infection.