Antiviral response by natural killer cells through TRAIL gene induction by IFN-alpha/beta.
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.
Sato
K
K
Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Tokyo, Japan.
Hida
S
S
Takayanagi
H
H
Yokochi
T
T
Kayagaki
N
N
Takeda
K
K
Yagita
H
H
Okumura
K
K
Tanaka
N
N
Taniguchi
T
T
Ogasawara
K
K
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
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