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

作　　者：Lifei Hou Zuliang Jie Yuejin Liang Mayura Desai Lynn Soong Jiaren Sun 

机构地区：[1]Department of Microbiology and Immunology, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA and [2]Department of Pathology, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA [3]These authors contributed equally to this work

出　　处：《Cellular & Molecular Immunology》2015年第2期213-221,共9页中国免疫学杂志（英文版）

摘　　要：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 I FN-I to orchestrate antiviral immune responses in the liver. Acute viral hepatitis was induced by i.v. injection of adenovirus （Ad） in IFN-a receptor knockout （IFNAR-/-） and control mice. To disrupt signaling, monoclonal antibodies （mAbs） against IL-7 receptor alpha （IL-7Re） 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-7 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-Ll-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.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 I FN-I to orchestrate antiviral immune responses in the liver. Acute viral hepatitis was induced by i.v. injection of adenovirus （Ad） in IFN-a receptor knockout （IFNAR-/-） and control mice. To disrupt signaling, monoclonal antibodies （mAbs） against IL-7 receptor alpha （IL-7Re） 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-7 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-Ll-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.

关 键 词：CD8＋ T cell INTERLEUKIN-7 PD-1 type 1 interferon viral hepatitis 

分 类 号：Q456[生物学—生理学] S858.32[农业科学—临床兽医学]