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

Shuye Zhang, Karen Kodys, Kui Li, G. Szabó

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

BACKGROUND & AIMS: The type III interferons (IFN- α s: 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.

Original languageEnglish
JournalGastroenterology
Volume144
Issue number2
DOIs
Publication statusPublished - Feb 2013

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Virus Diseases
Myeloid Cells
Hepacivirus
Dendritic Cells
Interferons
Interleukins
Blood Cells
Toll-Like Receptor 7
Toll-Like Receptor 3
Natural Killer T-Cells
Coculture Techniques
Virion
Hepatitis
Cell Culture Techniques
RNA
Cytokines
Antigens

Keywords

  • IL-28B SNP
  • NK cells
  • NKT cells
  • Viral immune regulation

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Human type 2 myeloid dendritic cells produce interferon-λ and amplify interferon-α in response to hepatitis C virus infection. / Zhang, Shuye; Kodys, Karen; Li, Kui; Szabó, G.

In: Gastroenterology, Vol. 144, No. 2, 02.2013.

Research output: Contribution to journalArticle

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abstract = "BACKGROUND & AIMS: The type III interferons (IFN- α s: 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.",
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AU - Szabó, G.

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N2 - BACKGROUND & AIMS: The type III interferons (IFN- α s: 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.

AB - BACKGROUND & AIMS: The type III interferons (IFN- α s: 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.

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KW - NK cells

KW - NKT cells

KW - Viral immune regulation

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