Interferon regulatory factor-1 (IRF-1) shapes both innate and CD8(+) T cell immune responses against West Nile virus infection

• Published in: PLoS pathogens 2011-09, Vol.7 (9), p.e1002230-e1002230
• Main Authors: Brien, James D, Daffis, Stephane, Lazear, Helen M, Cho, Hyelim, Suthar, Mehul S, Gale, Jr, Michael, Diamond, Michael S
• Format: Article
• Language: English
• Subjects: Adaptive Immunity - drug effects; Adaptive Immunity - immunology; Animals; B-Lymphocytes - immunology; Biology; CD8-Positive T-Lymphocytes - immunology; Cell culture; Cell Proliferation; Central Nervous System - cytology; Experiments; Flavivirus; Immunity, Innate - drug effects; Infections; Interferon Regulatory Factor-1 - deficiency; Interferon Regulatory Factor-1 - immunology; Interferon Regulatory Factor-1 - physiology; Interferon-beta - physiology; Interferon-gamma - drug effects; Interferon-gamma - physiology; Lymphocytes; Macrophages - immunology; Mice; Mice, Inbred C57BL; Peptides; Proteins; Regulation; Studies; West Nile Fever - immunology; West Nile virus; West Nile virus - immunology
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1002230

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.