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

• DOI: 10.1371/journal.ppat.1002230
• Publication Date: 2011-09-01T21:44:24Z
• Authors: James D. Brien; Stephane Daffis; Helen M. Lazear; Hyelim Cho; Mehul S. Suthar; Michael Gale; Michael S. Diamond
• Keywords: Central Nervous System; B-Lymphocytes; 0303 health sciences; QH301-705.5; Macrophages; Interferon-beta; RC581-607; Adaptive Immunity; CD8-Positive T-Lymphocytes; Immunity, Innate; 3. Good health; Mice, Inbred C57BL; Interferon-gamma; Mice; 03 medical and health sciences; Animals; Immunologic diseases. Allergy; Biology (General); West Nile virus; West Nile Fever; Research Article; Cell Proliferation; Interferon Regulatory Factor-1

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.