title: Type 1 interferon-induced IL-7 maintains CD8+ T-cell responses and homeostasis by suppressing PD-1 expression in viral hepatitis.
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.
authors.affiliation: Department of Microbiology and Immunology, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Lifei
authors.initials: L
authors.lastname: Hou
authors.affiliation: Department of Microbiology and Immunology, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Zuliang
authors.initials: Z
authors.lastname: Jie
authors.affiliation: Department of Microbiology and Immunology, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Yuejin
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Microbiology and Immunology, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Mayura
authors.initials: M
authors.lastname: Desai
authors.affiliation: 1] Department of Microbiology and Immunology, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA [2] Department of Pathology, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Soong
authors.affiliation: Department of Microbiology and Immunology, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Jiaren
authors.initials: J
authors.lastname: Sun
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D000998:Antiviral Agents / Q000494:pharmacology; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006505:Hepatitis / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D006706:Homeostasis; D007370:Interferon Type I / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism; D015851:Interleukin-7 / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D053633:Receptor, Interferon alpha-beta / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; C508032:Ifnar1 protein, mouse; D007370:Interferon Type I; D015851:Interleukin-7; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger; D053633:Receptor, Interferon alpha-beta; D007371:Interferon-gamma