Hepatitis C virus-induced natural killer cell proliferation involves monocyte-derived cells and the OX40/OX40L axis
Background & Aims Natural killer (NK) cells are found at increased frequencies in patients with hepatitis C virus (HCV). NK cell activation has been shown to correlate with HCV clearance and to predict a favourable treatment response. The aim of our study was to dissect mechanisms leading to NK...
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| Main Authors: | , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
2018
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| In: |
Journal of hepatology
Year: 2018, Volume: 68, Issue: 3, Pages: 421-430 |
| ISSN: | 1600-0641 |
| DOI: | 10.1016/j.jhep.2017.10.021 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1016/j.jhep.2017.10.021 Verlag, Volltext: http://www.sciencedirect.com/science/article/pii/S0168827817324005 
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| Author Notes: | Julia Pollmann, Jana-Julia Götz, Daniel Rupp, Otto Strauss, Markus Granzin, Oliver Grünvogel, Pascal Mutz, Catharina Kramer, Felix Lasitschka, Volker Lohmann, Niklas K. Björkström, Robert Thimme, Ralf Bartenschlager, Adelheid Cerwenka |
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| 245 | 1 | 0 | |a Hepatitis C virus-induced natural killer cell proliferation involves monocyte-derived cells and the OX40/OX40L axis |c Julia Pollmann, Jana-Julia Götz, Daniel Rupp, Otto Strauss, Markus Granzin, Oliver Grünvogel, Pascal Mutz, Catharina Kramer, Felix Lasitschka, Volker Lohmann, Niklas K. Björkström, Robert Thimme, Ralf Bartenschlager, Adelheid Cerwenka |
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| 520 | |a Background & Aims Natural killer (NK) cells are found at increased frequencies in patients with hepatitis C virus (HCV). NK cell activation has been shown to correlate with HCV clearance and to predict a favourable treatment response. The aim of our study was to dissect mechanisms leading to NK cell activation and proliferation in response to HCV. Methods: NK cell phenotype, proliferation, and function were assessed after the 6-day co-culture of human peripheral blood mononuclear cells with either HCV replicon-containing HuH6 hepatoblastoma cells or HCV-infected HuH7.5 cells. The results obtained were confirmed by immunohistochemistry of liver biopsies from patients with HCV and from HCV-negative controls. Results: In HCV-containing co-cultures, a higher frequency of NK cells upregulated the expression of the high-affinity IL-2 receptor chain CD25, proliferated more rapidly, and produced higher amounts of interferon γ compared with NK cells from control co-cultures. This NK cell activation was dependent on IL-2, cell-cell contact-mediated signals, and HCV replicon-exposed monocytes. The tumour necrosis factor-receptor superfamily member OX40 was induced on the activated CD25± NK cell subset and this induction was abrogated by the depletion of CD14+ monocytes. Moreover, OX40L was upregulated on CD14± monocyte-derived cells co-cultured with HCV-containing cells and also observed in liver biopsies from patients with HCV. Importantly, blocking of the OX40/OX40L interaction abolished both NK cell activation and proliferation. Conclusions: Our results uncover a previously unappreciated cell-cell contact-mediated mechanism of NK cell activation and proliferation in response to HCV, mediated by monocyte-derived cells and the OX40/OX40L axis. These results reveal a novel mode of crosstalk between innate immune cells during viral infection. Lay summary: Using a cell-culture model of hepatitis C virus (HCV) infection, our study revealed that natural killer (NK) cells become activated and proliferate when they are co-cultured with HCV-containing liver cells. The mechanism of this activation involves crosstalk with other innate immune cells and a cell-cell contact interaction mediated by the cell surface molecules OX40 and OX40L. Our study reveals a novel pathway leading to NK cell proliferation and activation against virus-infected cells that might be of relevance in antiviral immunity. | ||
| 650 | 4 | |a Hepatitis C virus | |
| 650 | 4 | |a Natural killer cells | |
| 650 | 4 | |a NK cell-monocyte crosstalk | |
| 650 | 4 | |a OX40 | |
| 650 | 4 | |a OX40L | |
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