IL-27-producing B cells are key regulators of anti-viral immunity and antibody responses

Abstract

Abstract Emerging evidence indicates that B lymphocytes regulate immunity by producing antibodies, presenting antigens and secreting cytokines that provide signals to other cells to modulate both humoral and cellular immunity. Here, we show that B cells produce IL-27 upon activation by TLR4 and CD40 in the presence of IL-21 in vitro. Using Lymphocytic choriomeningitis virus (LCMV) Clone 13 as a model of a persistent viral infection, we identify plasma B cells as major source of IL-27. Further, we show that IL-27-producing B cells are key players in the regulation of immunity. Mice with conditional B cell–specific IL-27p28 knockout were unable to control persistent LCMV infection and failed to respond to anti-IFNAR1 immunotherapy. The impaired immunity found in these mice was associated with reduced virus-specific IgG2a/2c. In addition, these mice displayed reduced virus-specific CD4+ T cells and T follicular helper (Tfh) cells, suggesting that B-cell-derived cytokines regulate immunity by providing signals to T cells. The effects of Il27ra deletion from T cells mirrors the phenotypes observed in mice lacking B-cell-derived IL-27. In addition, IL-27ra deficient (KO) Tfh cells lost their ability to produce IL-21, resulting in aberrant production of virus-specific antibodies to LCMV clone 13 in IL-27ra KO mice. Finally, RNA-sequencing of virus-specific CD4+ T cells identified IL-27R-dependent genes during persistent LCMV infection. Collectively, our data reveal a central role of plasma cell-derived IL-27 in the regulation of T cell functions. Importantly, our study describes cellular interactions between T and B cells and highlights the importance of virus-specific IgG2a/2c during persistent LCMV infection.