IFN-gamma production by human natural killer cells in response to HCV-infected hepatoma cells is dependent on accessory cells
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UMass Chan Affiliations
Department of Medicine, Division of GastroenterologyDocument Type
Journal ArticlePublication Date
2013-09-01Keywords
Interferon-gammaInterferon-alpha
Hepatovirus
Killer Cells, Natural
Hepatology
Immunology and Infectious Disease
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BACKGROUND and AIMS: Interferon-gamma (IFN-gamma), a cytokine produced by activated natural killer cell (NK) and T lymphocytes, is an important regulator of innate and adaptive immunity during hepatitis C virus (HCV) infection. However, the cellular sources and mechanisms of IFN-gamma induction in HCV-infection are not fully understood. METHODS: We cultured normal human peripheral blood mononuclear cells (PBMCs) with different populations of immune cells and JFH-1 HCV-infected Huh7.5 (JFH-1/Huh7.5) cells. RESULTS: We found that PBMCs produced large amounts of IFN-gamma after co-culture with JFH-1/Huh7.5 cells. Using intracellular cytokine staining we confirmed that NK cells and NKT cells (to a lesser extent) were the major IFN-gamma producers within PBMCs. Purified NK/NKT cells did not produce IFN-gamma in response to JFH-1/Huh7.5 cells and depletion of accessory (HLA-DR+) cells prevented IFN-gamma induction in PBMCs. Through selective cell depletion of dendritic cells or monocytes from PBMCs, we determined that plasmacytoid dendritic cells (pDCs) were indispensable for NK-IFN-gamma induction and the presence of monocytes was needed for maximal NK-IFN-gamma induction. We further revealed that NK-IFN-gamma induction depended on pDC-derived IFN-alpha while other IFN-gamma inducing cytokines, IL-12 and IL-18, played minimal roles. Close contact between JFH-1/Huh7.5 cells and NK cells was required for IFN-gamma production and monocyte-derived IL-15, significantly augmented IFN-gamma induction. CONCLUSIONS: We discovered a novel mechanism where NK cells interact with pDCs and monocytes, efficiently producing IFN-gamma in response to HCV-infected cells. This indicates that co-operation between NK cells and accessory cells is critical for IFN-gamma production and regulators of immunity during HCV infection.Source
J Hepatol. 2013 Sep;59(3):442-9. doi: 10.1016/j.jhep.2013.04.022. Link to article on publisher's siteDOI
10.1016/j.jhep.2013.04.022Permanent Link to this Item
http://hdl.handle.net/20.500.14038/30036PubMed ID
23665181Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1016/j.jhep.2013.04.022