Interferon Regulatory Factor-1 (IRF-1) Shapes Both Innate and CD8+ T Cell Immune Responses against West Nile Virus Infection

Interferon regulatory factor (IRF)-1 is an immunomodulatory transcription factor that functions downstream of pathogen recognition receptor signaling and has been implicated as a regulator of type I interferon (IFN)-αβ expression and the immune response to virus infections. However, this role for IRF-1 remains controversial because altered type I IFN responses have not been systemically observed in IRF-1 -/- mice. To evaluate the relationship of IRF-1 and immune regulation, we assessed West Nile virus (WNV) infectivity and the host response in IRF-1 -/- cells and mice. IRF-1 -/- mice were highly vulnerable to WNV infection with enhanced viral replication in peripheral tissues and rapid dissemination into the central nervous system. Ex vivo analysis revealed a cell-type specific antiviral role as IRF-1 -/- macrophages supported enhanced WNV replication but infection was unaltered in IRF-1 -/- fibroblasts. IRF-1 also had an independent and paradoxical effect on CD8+ T cell expansion. Although markedly fewer CD8+ T cells were observed in naïve animals as described previously, remarkably, IRF-1 -/- mice rapidly expanded their pool of WNV-specific cytolytic CD8+ T cells. Adoptive transfer and in vitro proliferation experiments established both cell-intrinsic and cell-extrinsic effects of IRF-1 on the expansion of CD8+ T cells. Thus, IRF-1 restricts WNV infection by modulating the expression of innate antiviral effector molecules while shaping the antigen-specific CD8+ T cell response.
Author Summary Interferon regulatory factor (IRF)-1 is a transcription factor that has been implicated in immune regulation and induction of type I IFN gene expression. To better understand the contribution of IRF-1 to antiviral immunity, we infected cells and mice lacking IRF-1 with West Nile virus (WNV), an encephalitic flavivirus. IRF-1 -/- mice were uniformly vulnerable to WNV infection with enhanced viral replication and rapid dissemination into the brain and spinal cord. Studies in cell culture revealed a cell-type specific antiviral role as IRF-1 -/- macrophages but not fibroblasts supported enhanced WNV replication. IRF-1 also had an independent effect on CD8+ T cell responses. Although fewer CD8+ T cells were observed in naïve animals, WNV-specific CD8+ T cells rapidly expanded in IRF-1 -/- mice and retained the capacity to clear infection. Collectively, our studies define independent roles for IRF-1 in restricting WNV pathogenesis and modulating the protective CD8+ T cell response.