Antiviral response by natural killer cells through TRAIL gene induction by IFN-alpha/beta

Eur J Immunol. 2001 Nov;31(11):3138-46. doi: 10.1002/1521-4141(200111)31:11<3138::aid-immu3138>;2-b.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins
  • Cardiovirus Infections / immunology*
  • Cytotoxicity, Immunologic*
  • DNA-Binding Proteins / physiology
  • Encephalomyocarditis virus / immunology*
  • Gene Expression Regulation
  • Interferon-Stimulated Gene Factor 3
  • Interferon-Stimulated Gene Factor 3, gamma Subunit
  • Interferon-alpha / physiology*
  • Interferon-beta / physiology*
  • Killer Cells, Natural / immunology*
  • Membrane Glycoproteins / genetics*
  • Membrane Glycoproteins / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, SCID
  • TNF-Related Apoptosis-Inducing Ligand
  • Transcription Factors / physiology
  • Transcriptional Activation
  • Tumor Necrosis Factor-alpha / genetics*
  • Tumor Necrosis Factor-alpha / physiology


  • Apoptosis Regulatory Proteins
  • DNA-Binding Proteins
  • Interferon-Stimulated Gene Factor 3
  • Interferon-Stimulated Gene Factor 3, gamma Subunit
  • Interferon-alpha
  • Isgf3g protein, mouse
  • Membrane Glycoproteins
  • TNF-Related Apoptosis-Inducing Ligand
  • Tnfsf10 protein, mouse
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • Interferon-beta