Viral IFN-regulatory factors inhibit activation-induced cell death via two positive regulatory IFN-regulatory factor 1-dependent domains in the CD95 ligand promoter

J Immunol. 2002 Feb 1;168(3):1226-34. doi: 10.4049/jimmunol.168.3.1226.

Abstract

The CD95 (also called APO-1/Fas) system plays a major role in the induction of apoptosis in lymphoid and nonlymphoid tissues. The CD95 ligand (CD95L) is induced in response to a variety of signals, including IFN-gamma and TCR/CD3 stimulation. Here we report the identification of two positive regulatory IFN-regulatory factor-dependent domains (PRIDDs) in the CD95L promoter and its 5' untranslated region, respectively. EMSAs demonstrate specific binding of IFN-gamma-induced IFN-regulatory factor 1 (IRF-1) to the PRIDD sequences. Ectopic IRF-1 expression induces CD95L promoter activity. Furthermore, we demonstrate that PRIDDs play an important role in TCR/CD3-mediated CD95L induction. Most interestingly, viral IRFs of human herpes virus 8 (HHV8) totally abolish IRF-1-mediated and strongly reduce TCR/CD3-mediated CD95L induction. We demonstrate here for the first time that viral IRFs inhibit activation-induced cell death. Thus, these results demonstrate an important mechanism of HHV8 to modulate the immune response by down-regulation of CD95L expression. Inhibition of CD95-dependent T cell function might contribute to the immune escape of HHV8.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / immunology*
  • DNA-Binding Proteins / physiology*
  • Down-Regulation / genetics
  • Down-Regulation / immunology
  • Fas Ligand Protein
  • Gene Expression Regulation / immunology
  • Genetic Vectors / biosynthesis
  • Genetic Vectors / immunology
  • HeLa Cells
  • Herpesvirus 8, Human / immunology
  • Humans
  • Immunosuppressive Agents / pharmacology*
  • Interferon Regulatory Factor-1
  • Interferon Regulatory Factors
  • Interferon-gamma / pharmacology
  • Jurkat Cells
  • Ligands
  • Lymphocyte Activation / immunology
  • Membrane Glycoproteins / biosynthesis
  • Membrane Glycoproteins / genetics*
  • Membrane Glycoproteins / metabolism
  • Mutagenesis, Site-Directed
  • Phosphoproteins / physiology*
  • Point Mutation
  • Promoter Regions, Genetic / immunology*
  • Protein Structure, Tertiary / genetics
  • Transcription Factors / physiology*
  • Viral Proteins / physiology*
  • fas Receptor / metabolism*

Substances

  • DNA-Binding Proteins
  • FASLG protein, human
  • Fas Ligand Protein
  • IRF1 protein, human
  • Immunosuppressive Agents
  • Interferon Regulatory Factor-1
  • Interferon Regulatory Factors
  • Ligands
  • Membrane Glycoproteins
  • Phosphoproteins
  • Transcription Factors
  • Viral Proteins
  • fas Receptor
  • viral interferon regulatory factors
  • Interferon-gamma