title: Chronic Type I IFN Is Sufficient To Promote Immunosuppression through Accumulation of Myeloid-Derived Suppressor Cells.
abstract: Failure of the immune system to eradicate viruses results in chronic viral infections, which are associated with increased susceptibility to secondary infections. Pathogenic HIV or lymphocytic choriomeningitis virus chronic infections display a persistent type I IFN signature. In chronic lymphocytic choriomeningitis virus infection, blockade of type I IFN signaling partially restores antiviral responses. In a mouse model, we tested whether chronic administration of type I IFN, at doses mimicking chronic viral infection, induced immunosuppression. Chronic exposure of mice to IFN-α alone was sufficient to strongly suppress specific CD8+T cells responses to subsequent vaccinia virus infection. It resulted in the accumulation of Ly6Chimonocytes. These monocytes were similar, phenotypically and functionally, to the myeloid-derived suppressor cells found in cancer because they exerted a potent suppression on CD8+T cell responses in vitro. They acted at least partly through the l-arginine pathway. In vivo, their elimination restored antiviral CD8+T cell responses. Our work provides a specific mechanism accounting for the role of IFN-α in immunosuppression and predicts that type I IFN modulation will be pivotal to cure human chronic infections, cancer, or autoimmune diseases.
authors.affiliation: INSERM, U1016, Institut Cochin, 75014 Paris, France.|CNRS UMR8104, 75014 Paris, France; and.|Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France.
authors.forename: Kahina
authors.identifier: 0000-0002-2560-2230
authors.initials: K
authors.lastname: Taleb
authors.affiliation: INSERM, U1016, Institut Cochin, 75014 Paris, France.|CNRS UMR8104, 75014 Paris, France; and.|Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Auffray
authors.affiliation: INSERM, U1016, Institut Cochin, 75014 Paris, France.|CNRS UMR8104, 75014 Paris, France; and.|Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Villefroy
authors.affiliation: INSERM, U1016, Institut Cochin, 75014 Paris, France.|CNRS UMR8104, 75014 Paris, France; and.|Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France.
authors.forename: Adrien
authors.identifier: 0000-0001-9688-8232
authors.initials: A
authors.lastname: Pereira
authors.affiliation: INSERM, U1016, Institut Cochin, 75014 Paris, France.|CNRS UMR8104, 75014 Paris, France; and.|Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France.
authors.forename: Anne
authors.identifier: 0000-0001-9021-3488
authors.initials: A
authors.lastname: Hosmalin
authors.affiliation: INSERM, U1016, Institut Cochin, 75014 Paris, France.|CNRS UMR8104, 75014 Paris, France; and.|Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Gaudry
authors.affiliation: INSERM, U1016, Institut Cochin, 75014 Paris, France; agnes.lebon@inserm.fr.|CNRS UMR8104, 75014 Paris, France; and agnes.lebon@inserm.fr.|Université Paris Descartes, Sorbonne Paris Cité, 75014 Paris, France agnes.lebon@inserm.fr.
authors.forename: Agnès
authors.identifier: 0000-0003-4204-8136
authors.initials: A
authors.lastname: Le Bon
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D007108:Immune Tolerance / Q000187:drug effects*; D007370:Interferon Type I / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D000072737:Myeloid-Derived Suppressor Cells / Q000187:drug effects* / Q000502:physiology; D014777:Virus Diseases / Q000276:immunology
chemical_list: D007370:Interferon Type I