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Cellular & Molecular Immunology (2015) 12, 213–221; doi:10.1038/cmi.2014.49; published online 14 July 2014
Type 1 interferon-induced IL-7 maintains CD8+ T-cell responses and homeostasis by suppressing PD-1 expression in viral hepatitis
Lifei Hou1,3, Zuliang Jie1,3, Yuejin Liang1,3, Mayura Desai1, Lynn Soong1,2 and Jiaren Sun1
1Department of Microbiology and Immunology, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA
2Department of Pathology, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA
Correspondence: Dr J Sun, Department of Microbiology and Immunology, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-1070, USA. E-mail: [email protected]
3These authors contributed equally to this work.
Received 10 April 2014; Revised 28 May 2014; Accepted 28 May 2014
Advance online publication 14 July 2014
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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.
Keywords:
CD8+ T cell; interleukin-7; PD-1; type 1 interferon; viral hepatitis
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发表于 2015-3-3 17:54
