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Type 1 interferon-induced IL-7 maintains CD8+ T-cell responses and homeostasis by suppressing PD-1 expression in viral hepatitis

Cellular & Molecular Immunology volume 12, pages 213–222 (2015)Cite this article

Abstract

Type 1 interferon (IFN-I) promotes antigen-presenting cell maturation and was recently shown to induce hepatic IL-7 production during infection. Herein, we further explored the underlying mechanisms used by IFN-I to orchestrate antiviral immune responses in the liver. Acute viral hepatitis was induced by i.v. injection of adenovirus (Ad) in IFN-α receptor knockout (IFNAR−/−) and control mice. To disrupt signaling, monoclonal antibodies (mAbs) against IL-7 receptor alpha (IL-7Rα) or PD-L1 were i.p. injected. We found that CD8+ T cells in IFNAR−/− mice were less effective than those in control mice. The reduced T-cell function was accompanied by increased levels of PD-1 expression, apoptosis and decreased IFN-γ production. The lack of IFN-I signaling also impaired the expression of accessory molecules in both intrahepatic dendritic cell (DCs) and hepatocytes. PD-L1 was comparably and highly expressed on hepatocytes in both IFNAR−/− and control mice. Injection of PD-L1-specific mAb in IFNAR−/− mice reversed the compromised immune responses in the liver. Further investigation showed that hepatic IL-7 elevation was less pronounced in IFNAR−/− mice compared to the controls. A treatment with recombinant IL-7 suppressed PD-1 expression on CD8+ T cells in vitro. Accordingly, blocking IL-7R signaling in vivo resulted in increased PD-1 expression on CD8+ T cells in Ad-infected mice. Collectively, the results suggest that IFN-I-induced hepatic IL-7 production maintains antiviral CD8+ T-cell responses and homeostasis by suppressing PD-1 expression in acute viral hepatitis.

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Acknowledgements

We thank Ms Mardelle Susman for her editorial assistance. None of the authors has a conflict of interest. LH, ZJ, YL and DM performed the experiments; LH, ZJ, YL, LS and JS analyzed the data: LH, YL, DM, LS and JS wrote the paper. This work was supported by the National Institutes of Health grant AI109100 (JS). ZJ was in part supported by the James W. McLaughlin Fellowship and the UTMB Graduate School of Biomedical Sciences.

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  1. Lifei Hou, Zuliang Jie and Yuejin Liang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Microbiology and Immunology, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA

    Lifei Hou, Zuliang Jie, Yuejin Liang, Mayura Desai, Lynn Soong & Jiaren Sun

  2. Department of Pathology, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA

    Lynn Soong

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  1. Lifei Hou
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Correspondence to Jiaren Sun.

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Hou, L., Jie, Z., Liang, Y. et al. Type 1 interferon-induced IL-7 maintains CD8+ T-cell responses and homeostasis by suppressing PD-1 expression in viral hepatitis. Cell Mol Immunol 12, 213–222 (2015). https://doi.org/10.1038/cmi.2014.49

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