title: Antiviral response by natural killer cells through TRAIL gene induction by IFN-alpha/beta.
abstract: Natural killer (NK) cells play an important role in early defense against viral infection. The cytotoxic activity of NK cells is increased by interferon-alpha/beta (IFN-alpha/beta), produced en masse in virally infected cells. However, the mechanism(s) by which IFN-alpha/beta contribute to the NK-cell-mediated antiviral response is not well understood. Here we provide evidence that the cytotoxicity of NK cells is enhanced by IFN-alpha/beta through induction of TNF-related apoptosis-inducing ligand (TRAIL). Isolation and analysis of the murine TRAIL promoter revealed the presence of an IFN-stimulated response element (ISRE), which binds to the transcription factor ISGF3 (interferon stimulated gene factor-3). This promoter is indeed activated by IFN-beta in ISGF3-dependent manner. We also show that virally infected cells, but not uninfected cells, are susceptible to TRAIL-mediated cytotoxicity in vitro, and that the TRAIL expressed in NK cells is indeed crucial in limiting virus replication in vivo. Thus, our study reveals a new molecular link between IFN-alpha/beta signaling and activation of NK cells in antiviral response of the host.
authors.affiliation: Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Sato
authors.forename: S
authors.initials: S
authors.lastname: Hida
authors.forename: H
authors.initials: H
authors.lastname: Takayanagi
authors.forename: T
authors.initials: T
authors.lastname: Yokochi
authors.forename: N
authors.initials: N
authors.lastname: Kayagaki
authors.forename: K
authors.initials: K
authors.lastname: Takeda
authors.forename: H
authors.initials: H
authors.lastname: Yagita
authors.forename: K
authors.initials: K
authors.lastname: Okumura
authors.forename: N
authors.initials: N
authors.lastname: Tanaka
authors.forename: T
authors.initials: T
authors.lastname: Taniguchi
authors.forename: K
authors.initials: K
authors.lastname: Ogasawara
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D018188:Cardiovirus Infections / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D004268:DNA-Binding Proteins / Q000502:physiology; D004686:Encephalomyocarditis virus / Q000276:immunology*; D005786:Gene Expression Regulation; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha / Q000502:physiology*; D016899:Interferon-beta / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D053221:TNF-Related Apoptosis-Inducing Ligand; D014157:Transcription Factors / Q000502:physiology; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha; C494228:Isgf3g protein, mouse; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta