title: Hepatitis C Virus-Induced Myeloid-Derived Suppressor Cells Suppress NK Cell IFN-γ Production by Altering Cellular Metabolism via Arginase-1.
abstract: The hepatitis C virus (HCV) infects ∼ 200 million people worldwide. The majority of infected individuals develop persistent infection, resulting in chronic inflammation and liver disease, including cirrhosis and hepatocellular carcinoma. The ability of HCV to establish persistent infection is partly due to its ability to evade the immune response through multiple mechanisms, including suppression of NK cells. NK cells control HCV replication during the early phase of infection and regulate the progression to chronic disease. In particular, IFN-γ produced by NK cells limits viral replication in hepatocytes and is important for the initiation of adaptive immune responses. However, NK cell function is significantly impaired in chronic HCV patients. The cellular and molecular mechanisms responsible for impaired NK cell function in HCV infection are not well defined. In this study, we analyzed the interaction of human NK cells with CD33(+) PBMCs that were exposed to HCV. We found that NK cells cocultured with HCV-conditioned CD33(+) PBMCs produced lower amounts of IFN-γ, with no effect on granzyme B production or cell viability. Importantly, this suppression of NK cell-derived IFN-γ production was mediated by CD33(+)CD11b(lo)HLA-DR(lo) myeloid-derived suppressor cells (MDSCs) via an arginase-1-dependent inhibition of mammalian target of rapamycin activation. Suppression of IFN-γ production was reversed by l-arginine supplementation, consistent with increased MDSC arginase-1 activity. These novel results identify the induction of MDSCs in HCV infection as a potent immune evasion strategy that suppresses antiviral NK cell responses, further indicating that blockade of MDSCs may be a potential therapeutic approach to ameliorate chronic viral infections in the liver.
authors.affiliation: Beirne Carter Center for Immunology Research, University of Virginia School of Medicine, Charlottesville, VA 22908; Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22908;
authors.forename: Celeste C
authors.identifier: http://orcid.org/0000-0002-0070-3924
authors.initials: CC
authors.lastname: Goh
authors.affiliation: Beirne Carter Center for Immunology Research, University of Virginia School of Medicine, Charlottesville, VA 22908; Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22908;
authors.forename: Krystal M
authors.initials: KM
authors.lastname: Roggerson
authors.affiliation: Beirne Carter Center for Immunology Research, University of Virginia School of Medicine, Charlottesville, VA 22908; Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22908; Wide River Institute of Immunology, Seoul National University, Gangwon 25159, Korea; and.
authors.forename: Hai-Chon
authors.initials: HC
authors.lastname: Lee
authors.affiliation: Department of Gastroenterology, University of Colorado Health Sciences Center, Aurora, CO 80045.
authors.forename: Lucy
authors.identifier: http://orcid.org/0000-0003-3347-4192
authors.initials: L
authors.lastname: Golden-Mason
authors.affiliation: Department of Gastroenterology, University of Colorado Health Sciences Center, Aurora, CO 80045.
authors.forename: Hugo R
authors.identifier: http://orcid.org/0000-0002-1110-6914
authors.initials: HR
authors.lastname: Rosen
authors.affiliation: Beirne Carter Center for Immunology Research, University of Virginia School of Medicine, Charlottesville, VA 22908; Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA 22908; ysh5e@virginia.edu.
authors.forename: Young S
authors.identifier: http://orcid.org/0000-0002-2698-9844
authors.initials: YS
authors.lastname: Hahn
mesh_terms: D001119:Arginase / Q000378:metabolism*; D001120:Arginine / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000821:virology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism / Q000821:virology; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D012323:RNA Processing, Post-Transcriptional; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D063268:Sialic Acid Binding Ig-like Lectin 3; D007371:Interferon-gamma; D001120:Arginine; D058570:TOR Serine-Threonine Kinases; D001119:Arginase
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