Human type 2 myeloid dendritic cells produce interferon-lambda and amplify interferon-alpha in response to hepatitis C virus infection

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Department of Medicine, Division of Gastroenterology

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Antiviral Agents; Cells, Cultured; Dendritic Cells; Enzyme-Linked Immunosorbent Assay; Hepacivirus; Hepatitis C Antibodies; Hepatitis C, Chronic; Humans; Immunity, Cellular; Interferon-alpha; Interferon-gamma; Interleukins; Myeloid Cells; RNA, Viral; Real-Time Polymerase Chain Reaction


Digestive System Diseases | Gastroenterology | Hepatology | Immunology of Infectious Disease | Immunopathology


BACKGROUND and AIMS: The type III interferons (IFN-lambdas: 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-lambda.

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-alpha, IFN-gamma, and IFN-lambda. 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-alpha, whereas natural killer and natural killer T cells were the main source of IFN-gamma 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-alpha and IFN-lambda were linked-IFN-lambda increased production of IFN-alpha by plasmacytoid DCs and IFN-alpha significantly increased production of IFN-lambda.

CONCLUSIONS: mDC2s are a major source of IFN-lambda 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-lambda therefore has an important role in HCV infection.

DOI of Published Version



Gastroenterology. 2013 Feb;144(2):414-425.e7. doi: 10.1053/j.gastro.2012.10.034. Epub 2012 Oct 23. Link to article on publisher's site

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