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Interferon regulatory factor-1 ( IRF-1 ) shapes both innate and CD 8 + 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)-ab 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 naı̈ve 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 antigenspecific CD8 T cell response. Citation: Brien JD, Daffis S, Lazear HM, Cho H, Suthar MS, et al. (2011) Interferon Regulatory Factor-1 (IRF-1) Shapes Both Innate and CD8 T Cell Immune Responses against West Nile Virus Infection. PLoS Pathog 7(9): e1002230. doi:10.1371/journal.ppat.1002230 Editor: Jean K. Lim, Mount Sinai School of Medicine, United States of America Received January 3, 2011; Accepted July 14, 2011; Published September 1, 2011 Copyright: 2011 Brien et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: NIH grants U54 AI081680 (Pacific Northwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research), U19 AI083019 (M.G. and M.S.D), and R01 AI074973 (M.G. and M.S.D.) supported this work. J.D.B., H.M.L, and M.S. were supported by NIH Training grants (T32-AI07163-30, T32AI007172, and T32-AI0074-11, respectively). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: diamond@borcim.wustl.edu