title: Interferon regulatory factor-1 (IRF-1) shapes both innate and CD8(+) T cell immune responses against West Nile virus infection.
abstract: 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.
authors: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors: James D
authors: JD
authors: Brien
authors: Stephane
authors: S
authors: Daffis
authors: Helen M
authors: HM
authors: Lazear
authors: Hyelim
authors: H
authors: Cho
authors: Mehul S
authors: MS
authors: Suthar
authors: Michael
authors: M
authors: Gale
authors: Michael S
authors: MS
authors: Diamond
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects / Q000276:immunology*; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D002490:Central Nervous System / Q000166:cytology; D007113:Immunity, Innate / Q000187:drug effects*; D050856:Interferon Regulatory Factor-1 / Q000172:deficiency / Q000276:immunology / Q000502:physiology*; D016899:Interferon-beta / Q000502:physiology; D007371:Interferon-gamma / Q000187:drug effects / Q000502:physiology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D014901:West Nile Fever / Q000276:immunology*; D014902:West Nile virus / Q000276:immunology
chemical_list: D050856:Interferon Regulatory Factor-1; D016899:Interferon-beta; D007371:Interferon-gamma