title: Viral IFN-regulatory factors inhibit activation-induced cell death via two positive regulatory IFN-regulatory factor 1-dependent domains in the CD95 ligand promoter.
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.
authors.affiliation: Tumor Immunology Program, Tumorvirus-Immunology, German Cancer Research Center, D-16920 Heidelberg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Kirchhoff
authors.forename: Thorsten
authors.initials: T
authors.lastname: Sebens
authors.forename: Sven
authors.initials: S
authors.lastname: Baumann
authors.forename: Andreas
authors.initials: A
authors.lastname: Krueger
authors.forename: Rainer
authors.initials: R
authors.lastname: Zawatzky
authors.forename: Min
authors.initials: M
authors.lastname: Li-Weber
authors.forename: Edgar
authors.initials: E
authors.lastname: Meinl
authors.forename: Frank
authors.initials: F
authors.lastname: Neipel
authors.forename: Bernhard
authors.initials: B
authors.lastname: Fleckenstein
authors.forename: Peter H
authors.initials: PH
authors.lastname: Krammer
mesh_terms: D017209:Apoptosis / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D053222:Fas Ligand Protein; D005786:Gene Expression Regulation / Q000276:immunology; D005822:Genetic Vectors / Q000096:biosynthesis / Q000276:immunology; D006367:HeLa Cells; D019288:Herpesvirus 8, Human / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D050856:Interferon Regulatory Factor-1; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma / Q000494:pharmacology; D019169:Jurkat Cells; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D010750:Phosphoproteins / Q000502:physiology*; D017354:Point Mutation; D011401:Promoter Regions, Genetic / Q000276:immunology*; D017434:Protein Structure, Tertiary / Q000235:genetics; D014157:Transcription Factors / Q000502:physiology*; D014764:Viral Proteins / Q000502:physiology*; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C494257:IRF1 protein, human; D007166:Immunosuppressive Agents; D050856:Interferon Regulatory Factor-1; D050835:Interferon Regulatory Factors; D008024:Ligands; D008562:Membrane Glycoproteins; D010750:Phosphoproteins; D014157:Transcription Factors; D014764:Viral Proteins; D019014:fas Receptor; C413486:viral interferon regulatory factors; D007371:Interferon-gamma