title: IFNL3 mediates interaction between innate immune cells: Implications for hepatitis C virus pathogenesis.
abstract: Common IFN lambda 3 (IFNL3) variants have been demonstrated to affect spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infection. The functional basis of these genetic variants has yet to be determined. Data examining the effect of IFNL3, specifically, in innate immune cells is lacking. Here, we determined the expression of IFNL3 and its receptor IFNLR1 in blood immune cell subsets and in HCV-infected livers. Next we assessed their sensitivity to IFNL3. All participants were genotyped for the IFNL3 SNPs rs8099917 and rs12979860. Importantly, unstimulated blood immune cells express significantly higher levels of IFNL3 than HCV liver biopsies. Plasmacytoid dendritic cells (pDCs) are the predominant producers of IFNLR1, especially in response to IFN-α. PBMCs, monocytes and pDCs all respond to IFNL3 based on MxA up-regulation. No differences in IFNL3 expression levels between rs8099917 or rs12979860 genotypes were detected. This is the first study to show peripheral blood pDCs to be the main producers of IFNL3, especially compared with HCV-infected livers. This makes innate immune cells the key players in determining the functional significance of INFL3 polymorphisms in patients with HCV.
authors.affiliation: Institute for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia koco2654@uni.sydney.edu.au.
authors.forename: Kate S
authors.initials: KS
authors.lastname: O'Connor
authors.affiliation: Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, Australia.
authors.forename: Golo
authors.initials: G
authors.lastname: Ahlenstiel
authors.affiliation: Institute for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, Australia.
authors.forename: Vijayaprakash
authors.initials: V
authors.lastname: Suppiah
authors.affiliation: Institute for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Schibeci
authors.affiliation: Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, Australia Centre for Infectious Diseases and Microbiology, Sydney Emerging infections and Biosecurity Institute, University of Sydney and Westmead Hospital, Sydney Australia.
authors.forename: Adrian
authors.initials: A
authors.lastname: Ong
authors.affiliation: Institute for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, Australia.
authors.forename: Reynold
authors.initials: R
authors.lastname: Leung
authors.affiliation: Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, Australia.
authors.forename: David
authors.initials: D
authors.lastname: van der Poorten
authors.affiliation: Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, Australia Centre for Infectious Diseases and Microbiology, Sydney Emerging infections and Biosecurity Institute, University of Sydney and Westmead Hospital, Sydney Australia.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Douglas
authors.affiliation: Department of Gastroenterology and Hepatology, Nepean Hospital, Sydney Australia.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Weltman
authors.affiliation: Institute for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia.
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Stewart
authors.affiliation: Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Liddle
authors.affiliation: Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, Australia.
authors.forename: Jacob
authors.initials: J
authors.lastname: George
authors.affiliation: Institute for Immunology and Allergy Research, Westmead Millennium Institute, University of Sydney, Sydney, Australia.
authors.forename: David R
authors.initials: DR
authors.lastname: Booth
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology; D015331:Cohort Studies; D003713:Dendritic Cells / Q000276:immunology; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics / Q000472:pathogenicity*; D006526:Hepatitis C / Q000235:genetics / Q000473:pathology* / Q000821:virology*; D006801:Humans; D007111:Immunity, Cellular / Q000502:physiology*; D007113:Immunity, Innate / Q000502:physiology*; D016898:Interferon-alpha / Q000494:pharmacology; D007372:Interferons; D007378:Interleukins / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D008099:Liver / Q000473:pathology / Q000821:virology; D018121:Receptors, Cytokine / Q000235:genetics / Q000276:immunology / Q000502:physiology; D017471:Receptors, Interferon; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D018121:Receptors, Cytokine; D017471:Receptors, Interferon; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C579640:IFNLR1 protein, human
keywords: IFN; IFNL3; hepatitis C; innate immunity