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Blockade of Immunosuppressive Cytokines Restores NK Cell Antiviral Function in Chronic Hepatitis B Virus Infection

Peppa, D; Micco, L; Javaid, A; Kennedy, PTF; Schurich, A; Dunn, C; Pallant, C; ... Maini, MK; + view all (2010) Blockade of Immunosuppressive Cytokines Restores NK Cell Antiviral Function in Chronic Hepatitis B Virus Infection. PLOS PATHOG , 6 (12) , Article e1001227. 10.1371/journal.ppat.1001227. Green open access

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Abstract

NK cells are enriched in the liver, constituting around a third of intrahepatic lymphocytes. We have previously demonstrated that they upregulate the death ligand TRAIL in patients with chronic hepatitis B virus infection (CHB), allowing them to kill hepatocytes bearing TRAIL receptors. In this study we investigated whether, in addition to their pathogenic role, NK cells have antiviral potential in CHB. We characterised NK cell subsets and effector function in 64 patients with CHB compared to 31 healthy controls. We found that, in contrast to their upregulated TRAIL expression and maintenance of cytolytic function, NK cells had a markedly impaired capacity to produce IFN-gamma in CHB. This functional dichotomy of NK cells could be recapitulated in vitro by exposure to the immunosuppressive cytokine IL-10, which was induced in patients with active CHB. IL-10 selectively suppressed NK cell IFN-gamma production without altering cytotoxicity or death ligand expression. Potent antiviral therapy reduced TRAIL-expressing CD56 bright NK cells, consistent with the reduction in liver inflammation it induced; however, it was not able to normalise IL-10 levels or the capacity of NK cells to produce the antiviral cytokine IFN-gamma. Blockade of IL-10 +/- TGF-beta restored the capacity of NK cells from both the periphery and liver of patients with CHB to produce IFN-gamma, thereby enhancing their non-cytolytic antiviral capacity. In conclusion, NK cells may be driven to a state of partial functional tolerance by the immunosuppressive cytokine environment in CHB. Their defective capacity to produce the antiviral cytokine IFN-gamma persists in patients on antiviral therapy but can be corrected in vitro by IL-10+/- TGF-beta blockade.

Type: Article
Title: Blockade of Immunosuppressive Cytokines Restores NK Cell Antiviral Function in Chronic Hepatitis B Virus Infection
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.ppat.1001227
Publisher version: http://dx.doi.org/10.1371/journal.ppat.1001227
Language: English
Additional information: Copyright: © 2010 Peppa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was funded by Medical Research Council Awards G108515 and G0801213 to MKM, a CRDC Fellowship to DP and an EASL Fellowship to LM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Keywords: NATURAL-KILLER-CELLS, GENE PROMOTER POLYMORPHISMS, INTERFERON-GAMMA PRODUCTION, NECROSIS-FACTOR-ALPHA, T-CELLS, IN-VIVO, LIVER-DAMAGE, INTERLEUKIN-10, CYTOTOXICITY, INHIBITION
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute for Global Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute for Global Health > Infection and Population Health
URI: http://discovery.ucl.ac.uk/id/eprint/703795
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