title: Human type 2 myeloid dendritic cells produce interferon-λ and amplify interferon-α in response to hepatitis C virus infection.
abstract: OBJECTIVE
  The type III interferons (IFN-λs: interleukin [IL]-28a, IL-28b, and IL-29) have important roles in hepatitis C virus (HCV) infection, but little is understood about what cells produce these cytokines or how production is activated. We investigated whether human immune cells recognize HCV-infected cells and respond by producing IFN-λ.
  
  
  METHODS
  We cultured healthy human peripheral blood mononuclear cells (PBMCs) with different populations of immune cells and Japanese fulminant hepatitis-1 (JFH-1) HCV-infected Huh7.5 (cell culture-derived HCV particles [HCVcc]/Huh7.5) cells.
  
  
  RESULTS
  Human PBMCs recognized HCVcc/Huh7.5 cells and responded by producing IFN-α, IFN-γ, and IFN-λ. A rare subset of myeloid dendritic cells (mDCs), which are blood DC antigen (BDCA)+ (also called mDC2 cells), were the major source of IL-28 and IL-29 production in response to HCVcc/Huh7.5 cells. Plasmacytoid DCs produced IFN-α, whereas natural killer and natural killer T cells were the main source of IFN-γ production in co-culture experiments. Of the endosomal Toll-like receptors (TLRs)3, 7, 8, and 9, only TLR3 or double-stranded HCV RNA induced production of IL-28 and IL-29 by mDC2s; endosomal maturation was required. Production of IFN-α and IFN-λ were linked-IFN-λ increased production of IFN-α by plasmacytoid DCs and IFN-α significantly increased production of IFN-λ.
  
  
  CONCLUSIONS
  mDC2s are a major source of IFN-λ production by PBMCs in response to HCVcc/Huh7.5 cells. mDC2s are activated through the TLR3 pathway, indicating that human DCs efficiently can initiate an immune response against HCV infection. IFN-λ therefore has an important role in HCV infection.
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Shuye
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Karen
authors.initials: K
authors.lastname: Kodys
authors.affiliation: Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Kui
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts. Electronic address: gyongyi.szabo@umassmed.edu.
authors.forename: Gyongyi
authors.initials: G
authors.lastname: Szabo
mesh_terms: D000998:Antiviral Agents; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D016174:Hepacivirus / Q000276:immunology*; D018937:Hepatitis C Antibodies / Q000032:analysis*; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D006801:Humans; D007111:Immunity, Cellular; D016898:Interferon-alpha / Q000096:biosynthesis*; D007371:Interferon-gamma / Q000096:biosynthesis*; D007372:Interferons; D007378:Interleukins / Q000096:biosynthesis; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism*; D012367:RNA, Viral / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D018937:Hepatitis C Antibodies; D016898:Interferon-alpha; D007371:Interferon-gamma; D007372:Interferons; D007378:Interleukins; D012367:RNA, Viral; C000624353:interferon-lambda, human; D000095022:Interferon Lambda