Influenza A Virus-Induced IFN-α/β and IL-18 Synergistically Enhance IFN-γ Gene Expression in Human T Cells

Abstract T cells contribute significantly the to host’s early defense against viral and bacterial infections and are essential for clearance of the pathogen. IFN-γ, a product of activated T and NK cells, has, in addition to its direct antimicrobial activity, a major role in activating cell-mediated immunity. Here we report that cytokines secreted by influenza A virus-infected macrophages are able to induce IFN-γ synthesis in human T cells. Influenza A virus-infected human peripheral macrophages secreted IFN-α/β, TNF-α, IL-1β, and a recently identified cytokine, IL-18 (or IFN-γ-inducing factor), whereas the production of IL-12 was not detected. Supernatants collected from virus-infected macrophages induced rapid IFN-γ mRNA expression and protein production in T cells. This was down-regulated by the addition of neutralizing anti-IFN-α/β Abs, whereas neutralizing anti-IL-12 Abs had no effect on IFN-γ gene expression. Exogenously added IFN-α/β also rapidly stimulated the synthesis of IFN-γ mRNA in T cells independently of protein synthesis. IL-18 synergized with IFN-α to up-regulate IFN-γ gene expression and protein production. The data suggest that IFN-α/β and IL-18 produced by macrophages during virus infection may act together to induce IFN-γ synthesis and, consequently, may play an important role for both of these cytokines in the development of Th1-type immune responses.