IFN-γ production by human natural killer cells in response to HCV-infected hepatoma cells is dependent on accessory cells

JOURNAL OF HEPATOLOGY

卷:59

Article

Zhang, Shuye^1,2,3,4  Saha, Banishree¹  Kodys, Karen¹  Szabo, Gyongyi¹ 

[1] Univ Massachusetts, Sch Med, Worcester, MA 01605 USA

[2] Fudan Univ, Shanghai Publ Hlth Clin Ctr, Shanghai 200433, Peoples R China

[3] Fudan Univ, Inst Biomed Sci, Shanghai 200433, Peoples R China

[4] Fudan Univ, Key Lab Med Mol Virol, Inst Med Microbiol, Shanghai Med Coll, Shanghai 200433, Peoples R China

关键词: NK;    pDC;    Monocyte;    IFN-alpha;   

DOI  :  10.1016/j.jhep.2013.04.022

来源: Elsevier

【 摘 要 】

Background & Aims: Interferon-gamma (IFN-gamma), a cytokine produced by activated natural killer cells (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 regulation of immunity during HCV infection. (C) 2013 European Association for the Study of the Liver. Published by Elsevier B. V. All rights reserved.

【 授权许可】

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