研究文章Blockade of Immunosuppressive Cytokines Restores NK Cell Antiviral F

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A research article - 一个研究文章

Blockade of Immunosuppressive Cytokines Restores NK Cell Antiviral Function in Chronic Hepatitis B Virus Infectionhttp://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1001227

Dimitra Peppa1,2, Lorenzo Micco1, Alia Javaid3, Patrick T. F. Kennedy3, Anna Schurich1, Claire Dunn1, Celeste Pallant1, Gidon Ellis1, Pooja Khanna1,4, Geoffrey Dusheiko4, Richard J. Gilson2, Mala K. Maini1,2,3*

1 Division of Infection and Immunity, UCL, London, United Kingdom, 2 Centre for Sexual Health and HIV Research, UCL, London, United Kingdom, 3 Centre for Digestive Disease, Barts and The London School of Medicine and Dentistry, London, United Kingdom, 4 Centre for Hepatology, Hampstead Campus, Royal Free & University College Medical School, London, United Kingdom

Abstract TopNKcells are enriched in the liver, constituting around a third ofintrahepatic lymphocytes. We have previously demonstrated that theyupregulate the death ligand TRAIL in patients with chronic hepatitis Bvirus infection (CHB), allowing them to kill hepatocytes bearing TRAILreceptors. In this study we investigated whether, in addition to theirpathogenic role, NK cells have antiviral potential in CHB. Wecharacterised NK cell subsets and effector function in 64 patients withCHB compared to 31 healthy controls. We found that, in contrast totheir upregulated TRAIL expression and maintenance of cytolyticfunction, NK cells had a markedly impaired capacity to produce IFN-γ inCHB. This functional dichotomy of NK cells could be recapitulated in vitroby exposure to the immunosuppressive cytokine IL-10, which was inducedin patients with active CHB. IL-10 selectively suppressed NK cell IFN-γproduction without altering cytotoxicity or death ligand expression.Potent antiviral therapy reduced TRAIL-expressing CD56brightNK cells, consistent with the reduction in liver inflammation itinduced; however, it was not able to normalise IL-10 levels or thecapacity of NK cells to produce the antiviral cytokine IFN-γ. Blockadeof IL-10 +/− TGF-β restored the capacity of NK cells from both theperiphery and liver of patients with CHB to produce IFN-γ, therebyenhancing their non-cytolytic antiviral capacity. In conclusion, NKcells may be driven to a state of partial functional tolerance by theimmunosuppressive cytokine environment in CHB. Their defective capacityto produce the antiviral cytokine IFN-γ persists in patients onantiviral therapy but can be corrected in vitro by IL-10+/− TGF-βblockade.

Author Summary TopHepatitisB virus (HBV) infection is responsible for more than a million deathsannually as a result of the immune-mediated chronic liver damage itinduces. One of the key immune players in the liver is the naturalkiller (NK) cell, which we have recently found can cause liver damagein HBV infection. Here we address the antiviral potential of NK cellsin the HBV-infected liver and demonstrate that they have a specificimpairment in their ability to produce the cytokine IFN-γ, which couldlimit their capacity to control HBV. We find that the potent antiviraldrugs currently being used to treat HBV infection are unable to fullyreverse this NK cell functional defect. We define a role for theimmunosuppressive cytokine environment in HBV in down-regulating NKcell antiviral function, which can be restored by specific blockade ofIL-10 and TGF-β. This work therefore highlights a mechanismcontributing to the failure of immune control in chronic HBV infection,paving the way to new therapeutic options.






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