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Immune outcomes in the liver: Is CD8 T cell fate determined by the environment?

  • Yik Chun Wong
    Correspondence
    Corresponding authors. Address: Centenary Institute, Locked Bag No. 6, Newtown, NSW 2042, Australia. Tel.: +61 2 9565 6186; fax: +61 2 9565 6101.
    Affiliations
    Liver Immunology Group, Centenary Institute and AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia
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  • Author Footnotes
    ‡ Current address: Gene Therapy Research Unit, Children’s Medical Research Institute and The Children’s Hospital at Westmead, Westmead, NSW, Australia.
    Szun Szun Tay
    Footnotes
    ‡ Current address: Gene Therapy Research Unit, Children’s Medical Research Institute and The Children’s Hospital at Westmead, Westmead, NSW, Australia.
    Affiliations
    Liver Immunology Group, Centenary Institute and AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia
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  • Geoffrey W. McCaughan
    Affiliations
    Liver Cancer and Injury Group, Centenary Institute and AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia
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  • Author Footnotes
    † These authors contributed equally to this manuscript.
    David G. Bowen
    Footnotes
    † These authors contributed equally to this manuscript.
    Affiliations
    Liver Immunology Group, Centenary Institute and AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia
    Search for articles by this author
  • Author Footnotes
    † These authors contributed equally to this manuscript.
    Patrick Bertolino
    Correspondence
    Corresponding authors. Address: Centenary Institute, Locked Bag No. 6, Newtown, NSW 2042, Australia. Tel.: +61 2 9565 6186; fax: +61 2 9565 6101.
    Footnotes
    † These authors contributed equally to this manuscript.
    Affiliations
    Liver Immunology Group, Centenary Institute and AW Morrow Gastroenterology and Liver Centre, University of Sydney and Royal Prince Alfred Hospital, Sydney, NSW, Australia
    Search for articles by this author
  • Author Footnotes
    † These authors contributed equally to this manuscript.
    ‡ Current address: Gene Therapy Research Unit, Children’s Medical Research Institute and The Children’s Hospital at Westmead, Westmead, NSW, Australia.

      Summary

      The liver is known for its tolerogenic properties. This unique characteristic is associated with persistent infection of the liver by the hepatitis B and C viruses. Improper activation of cellular adaptive immune responses within the liver and immune exhaustion over time both contribute to ineffective cytotoxic T cell responses to liver-expressed antigens in animal models, and likely play a role in incomplete clearance of chronic hepatitis virus infections in humans. However, under some conditions, functional immune responses can be elicited against hepatic antigens, resulting in control of hepatotropic infections. In order to develop improved therapeutics in immune-mediated chronic liver diseases, including viral hepatitis, it is essential to understand how intrahepatic immunity is regulated. This review focuses on CD8 T cell immunity directed towards foreign antigens expressed in the liver, and explores how the liver environment dictates the outcome of intrahepatic CD8 T cell responses. Potential strategies to rescue unresponsive CD8 T cells in the liver are also discussed.

      Abbreviations:

      APCs (antigen-presenting cells), CTLs (cytotoxic CD8 T cells), DCs (dendritic cells), HBV (hepatitis B virus), HCV (hepatitis C virus), ICAM-1 (intercellular adhesion molecule-1), IL (interleukin), LCMV (lymphocytic choriomeningitis virus), LNs (lymph nodes), LSECs (liver sinusoidal endothelial cells), MHC-I (major histocompatibility complex class I), PD-1 (programmed death 1), PD-L1 (programmed death ligand-1), PD-L2 (programmed death ligand-2), rAAV (recombinant adeno-associated virus), TCR (T cell receptor), TLR (toll-like receptor)

      Keywords

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      References

        • Benseler V.
        • McCaughan G.W.
        • Schlitt H.J.
        • Bishop G.A.
        • Bowen D.G.
        • Bertolino P.
        The liver: a special case in transplantation tolerance.
        Semin Liver Dis. 2007; 27: 194-213
        • Triger D.R.
        • Cynamon M.H.
        • Wright R.
        Studies on hepatic uptake of antigen. I. Comparison of inferior vena cava and portal vein routes of immunization.
        Immunology. 1973; 25: 941-950
        • Mingozzi F.
        • Liu Y.-L.
        • Dobrzynski E.
        • Kaufhold A.
        • Liu J.H.
        • Wang Y.
        • et al.
        Induction of immune tolerance to coagulation factor IX antigen by in vivo hepatic gene transfer.
        J Clin Invest. 2003; 111: 1347-1356
        • Harty J.T.
        • Tvinnereim A.R.
        • White D.W.
        CD8+ T cell effector mechanisms in resistance to infection.
        Annu Rev Immunol. 2000; 18: 275-308
        • Thimme R.
        • Wieland S.
        • Steiger C.
        • Ghrayeb J.
        • Reimann K.A.
        • Purcell R.H.
        • et al.
        CD8+ T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection.
        J Virol. 2003; 77: 68-76
        • Bowen D.G.
        • Walker C.M.
        Adaptive immune responses in acute and chronic hepatitis C virus infection.
        Nature. 2005; 436: 946-952
        • Boni C.
        • Fisicaro P.
        • Valdatta C.
        • Amadei B.
        • Di Vincenzo P.
        • Giuberti T.
        • et al.
        Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection.
        J Virol. 2007; 81: 4215-4225
        • Webster G.J.M.
        • Reignat S.
        • Brown D.
        • Ogg G.S.
        • Jones L.
        • Seneviratne S.L.
        • et al.
        Longitudinal analysis of CD8+ T cells specific for structural and nonstructural hepatitis B virus proteins in patients with chronic hepatitis B: implications for immunotherapy.
        J Virol. 2004; 78: 5707-5719
        • Sobao Y.
        • Tomiyama H.
        • Sugi K.
        • Tokunaga M.
        • Ueno T.
        • Saito S.
        • et al.
        The role of hepatitis B virus-specific memory CD8 T cells in the control of viral replication.
        J Hepatol. 2002; 36: 105-115
        • Penna A.
        • Pilli M.
        • Zerbini A.
        • Orlandini A.
        • Mezzadri S.
        • Sacchelli L.
        • et al.
        Dysfunction and functional restoration of HCV-specific CD8 responses in chronic hepatitis C virus infection.
        Hepatology. 2007; 45: 588-601
        • Zinkernagel R.M.
        • Doherty P.C.
        Immunological surveillance against altered self components by sensitised T lymphocytes in lymphocytes choriomeningitis.
        Nature. 1974; 251: 547-548
        • Townsend A.R.M.
        • Rothbard J.
        • Gotch F.M.
        • Bahadur G.
        • Wraith D.
        • McMichael A.J.
        The epitopes of influenza nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides.
        Cell. 1986; 44: 959-968
        • Blum J.S.
        • Wearsch P.A.
        • Cresswell P.
        Pathways of antigen processing.
        Annu Rev Immunol. 2013; 31: 443-473
        • Nierkens S.
        • Tel J.
        • Janssen E.
        • Adema G.J.
        Antigen cross-presentation by dendritic cell subsets: one general or all sergeants?.
        Trends Immunol. 2013; 34: 361-370
        • Smith-Garvin J.E.
        • Koretzky G.A.
        • Jordan M.S.
        T cell activation.
        Annu Rev Immunol. 2009; 27: 591-619
        • Denton A.E.
        • Wesselingh R.
        • Gras S.
        • Guillonneau C.
        • Olson M.R.
        • Mintern J.D.
        • et al.
        Affinity thresholds for naive CD8+ CTL activation by peptides and engineered influenza A viruses.
        J Immunol. 2011; 187: 5733-5744
        • Zehn D.
        • Lee S.Y.
        • Bevan M.J.
        Complete but curtailed T-cell response to very low-affinity antigen.
        Nature. 2009; 458: 211-214
        • Chen L.
        • Flies D.B.
        Molecular mechanisms of T cell co-stimulation and co-inhibition.
        Nat Rev Immunol. 2013; 13: 227-242
        • Reis e Sousa C.
        Dendritic cells in a mature age.
        Nat Rev Immunol. 2006; 6: 476-483
        • Odorizzi P.M.
        • Wherry E.J.
        Inhibitory receptors on lymphocytes: insights from infections.
        J Immunol. 2012; 188: 2957-2965
        • Carter L.L.
        • Fouser L.A.
        • Jussif J.
        • Fitz L.
        • Deng B.
        • Wood C.R.
        • et al.
        PD-1:PD-L inhibitory pathway affects both CD4+ and CD8+ T cells and is overcome by IL-2.
        Eur J Immunol. 2002; 32: 634-643
        • Freeman G.J.
        • Long A.J.
        • Iwai Y.
        • Bourque K.
        • Chernova T.
        • Nishimura H.
        • et al.
        Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation.
        J Exp Med. 2000; 192: 1027-1034
        • Latchman Y.
        • Wood C.R.
        • Chernova T.
        • Chaudhary D.
        • Borde M.
        • Chernova I.
        • et al.
        PD-L2 is a second ligand for PD-1 and inhibits T cell activation.
        Nat Immunol. 2001; 2: 261-268
        • Walker L.S.K.
        • Sansom D.M.
        The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses.
        Nat Rev Immunol. 2011; 11: 852-863
        • Curtsinger J.M.
        • Schmidt C.S.
        • Mondino A.
        • Lins D.C.
        • Kedl R.M.
        • Jenkins M.K.
        • et al.
        Inflammatory cytokines provide a third signal for activation of naive CD4+ and CD8+ T cells.
        J Immunol. 1999; 162: 3256-3262
        • Curtsinger J.M.
        • Lins D.C.
        • Mescher M.F.
        Signal 3 determines tolerance versus full activation of baive CD8 T cells: dissociating proliferation and development of effector function.
        J Exp Med. 2003; 197: 1141-1151
        • Curtsinger J.M.
        • Valenzuela J.O.
        • Agarwal P.
        • Lins D.
        • Mescher M.F.
        Cutting edge: type I IFNs provide a third signal to CD8 T cells to stimulate clonal expansion and differentiation.
        J Immunol. 2005; 174: 4465-4469
        • Le Bon A.
        • Durand V.
        • Kamphuis E.
        • Thompson C.
        • Bulfone-Paus S.
        • Rossmann C.
        • et al.
        Direct stimulation of T cells by type I IFN enhances the CD8+ T cell response during cross-priming.
        J Immunol. 2006; 176: 4682-4689
        • Bachmann M.F.
        • McKall-Faienza K.
        • Schmits R.
        • Bouchard D.
        • Beach J.
        • Speiser D.E.
        • et al.
        Distinct roles for LFA-1 and CD28 during activation of naive T cells: adhesion versus costimulation.
        Immunity. 1997; 7: 549-557
        • Chirathaworn C.
        • Kohlmeier J.E.
        • Tibbetts S.A.
        • Rumsey L.M.
        • Chan M.A.
        • Benedict S.H.
        Stimulation through intercellular adhesion molecule-1 provides a second signal for T cell activation.
        J Immunol. 2002; 168: 5530-5537
        • Schoenberger S.P.
        • Toes R.E.M.
        • van der Voort E.I.H.
        • Offringa R.
        • Melief C.J.M.
        T-cell help for cytotoxic lymphocytes is mediated by CD40-CD40L interactions.
        Nature. 1998; 393: 480-483
        • Bennett S.R.M.
        • Carbone F.R.
        • Karamalis F.
        • Flavell R.A.
        • Miller J.F.A.P.
        • Heath W.R.
        Help for cytotoxic-T-cell responses is mediated by CD40 signalling.
        Nature. 1998; 393: 478-480
        • Smith C.M.
        • Wilson N.S.
        • Waithman J.
        • Villadangos J.A.
        • Carbone F.R.
        • Heath W.R.
        • et al.
        Cognate CD4+ T cell licensing of dendritic cells in CD8+ T cell immunity.
        Nat Immunol. 2004; 5: 1143-1148
        • Ridge J.P.
        • Di Rosa F.
        • Matzinger P.
        A conditioned dendritic cell can be a bridge between CD4+ T-helper and a T-killer cell.
        Nature. 1998; 393: 474-478
        • Williams M.A.
        • Bevan M.J.
        Effector and memory CTL differentiation.
        Annu Rev Immunol. 2007; 25: 171-192
        • Sun J.C.
        • Bevan M.J.
        Defective CD8 T cell memory following acute infection without CD4 T cell help.
        Science. 2003; 300: 339-342
        • Sun J.C.
        • Williams M.A.
        • Bevan M.J.
        CD4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection.
        Nat Immunol. 2004; 5: 927-933
        • Shedlock D.J.
        • Shen H.
        Requirement for CD4 T cell help in generating functional CD8 T cell memory.
        Science. 2003; 300: 337-339
        • von Boehmer H.
        Mechanisms of suppression by suppressor T cells.
        Nat Immunol. 2005; 6: 338-344
        • Bertolino P.
        • Bowen D.G.
        • McCaughan G.W.
        • Fazekas de St Groth B.
        Antigen-specific primary activation of CD8+ T cells within the liver.
        J Immunol. 2001; 166: 5430-5438
        • Morimoto J.
        • Tan X.
        • Teague R.M.
        • Öhlén C.
        • Greenberg P.D.
        Induction of tolerance in CD8+ T cells to a transgenic autoantigen expressed in the liver does not require cross-presentation.
        J Immunol. 2007; 178: 6849-6860
        • Klein I.
        • Crispe I.N.
        Complete differentiation of CD8+ T cells activated locally within the transplanted liver.
        J Exp Med. 2006; 203: 437-447
        • Wuensch S.A.
        • Pierce R.H.
        • Crispe I.N.
        Local intrahepatic CD8+ T cell activation by a non-self-antigen results in full functional differentiation.
        J Immunol. 2006; 177: 1689-1697
        • Derkow K.
        • Loddenkemper C.
        • Mintern J.
        • Kruse N.
        • Klugewitz K.
        • Berg T.
        • et al.
        Differential priming of CD8 and CD4 T-cells in animal models of autoimmune hepatitis and cholangitis.
        Hepatology. 2007; 46: 1155-1165
        • Park S.
        • Murray D.
        • John B.
        • Crispe I.N.
        Biology and significance of T-cell apoptosis in the liver.
        Immunol Cell Biol. 2002; 80: 74-83
        • Lalor P.F.
        • Shields P.
        • Grant A.J.
        • Adams D.H.
        Recruitment of lymphocytes to the human liver.
        Immunol Cell Biol. 2002; 80: 52-64
        • Bertolino P.
        • McCaughan G.W.
        • Bowen D.G.
        Role of primary intrahepatic T-cell activation in the ‘liver tolerance effect’.
        Immunol Cell Biol. 2002; 80: 84-92
        • Huang L.-R.
        • Wohlleber D.
        • Reisinger F.
        • Jenne C.N.
        • Cheng R.-L.
        • Abdullah Z.
        • et al.
        Intrahepatic myeloid-cell aggregates enable local proliferation of CD8+ T cells and successful immunotherapy against chronic viral liver infection.
        Nat Immunol. 2013; 14: 574-583
        • Bertolino P.
        • Bowen D.G.
        Malaria and the liver: immunological hide-and-seek or subversion of immunity from within?.
        Front Microbiol. 2015; 6: 41
        • Thomson A.W.
        • Knolle P.A.
        Antigen-presenting cell function in the tolerogenic liver environment.
        Nat Rev Immunol. 2010; 10: 753-766
        • Crispe I.N.
        Liver antigen-presenting cells.
        J Hepatol. 2011; 54: 357-365
        • Lohse A.W.
        • Knolle P.A.
        • Bilo K.
        • Uhrig A.
        • Waldmann C.
        • Ibe M.
        • et al.
        Antigen-presenting function and B7 expression of murine sinusoidal endothelial cells and Kupffer cells.
        Gastroenterology. 1996; 110: 1175-1181
        • Bertolino P.
        • Trescol-Biémont M.-C.
        • Rabourdin-Combe C.
        Hepatocytes induce functional activation of naive CD8+ T lymphocytes but fail to promote survival.
        Eur J Immunol. 1998; 28: 221-236
        • Katz S.C.
        • Pillarisetty V.G.
        • Bleier J.I.
        • Shah A.B.
        • DeMatteo R.P.
        Liver sinusoidal endothelial cells are insufficient to activate T cells.
        J Immunol. 2004; 173: 230-235
        • Yu M.-C.
        • Chen C.-H.
        • Liang X.
        • Wang L.
        • Gandhi C.R.
        • Fung J.J.
        • et al.
        Inhibition of T-cell responses by hepatic stellate cells via B7–H1–mediated T-cell apoptosis in mice.
        Hepatology. 2004; 40: 1312-1321
        • Holz L.E.
        • Benseler V.
        • Bowen D.G.
        • Bouillet P.
        • Strasser A.
        • O’Reilly L.
        • et al.
        Intrahepatic murine CD8 T-cell activation associates with a distinct phenotype leading to Bim-dependent death.
        Gastroenterology. 2008; 135: 989-997
        • Iwai Y.
        • Terawaki S.
        • Ikegawa M.
        • Okazaki T.
        • Honjo T.
        PD-1 inhibits antiviral immunity at the effector phase in the liver.
        J Exp Med. 2003; 198: 39-50
        • Mühlbauer M.
        • Fleck M.
        • Schütz C.
        • Weiss T.
        • Froh M.
        • Blank C.
        • et al.
        PD-L1 is induced in hepatocytes by viral infection and by interferon-α and -γ and mediates T cell apoptosis.
        J Hepatol. 2006; 45: 520-528
        • Maier H.
        • Isogawa M.
        • Freeman G.J.
        • Chisari F.V.
        PD-1:PD-L1 interactions contribute to the functional suppression of virus-specific CD8+ T lymphocytes in the liver.
        J Immunol. 2007; 178: 2714-2720
        • Diehl L.
        • Schurich A.
        • Grochtmann R.
        • Hegenbarth S.
        • Chen L.
        • Knolle P.A.
        Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance.
        Hepatology. 2008; 47: 296-305
        • Schurich A.
        • Berg M.
        • Stabenow D.
        • Böttcher J.
        • Kern M.
        • Schild H.-J.
        • et al.
        Dynamic regulation of CD8 T cell tolerance induction by liver sinusoidal endothelial cells.
        J Immunol. 2010; 184: 4107-4114
        • Bissell D.M.
        • Wang S.S.
        • Jarnagin W.R.
        • Roll F.J.
        Cell-specific expression of transforming growth factor-β in rat liver. Evidence for autocrine regulation of hepatocyte proliferation.
        J Clin Invest. 1995; 96: 447-455
        • De Bleser P.J.
        • Niki T.
        • Rogiers V.
        • Geerts A.
        Transforming growth factor-β gene expression in normal and fibrotic rat liver.
        J Hepatol. 1997; 26: 886-893
        • Knolle P.A.
        • Uhrig A.
        • Protzer U.
        • Trippler M.
        • Duchmann R.
        • Meyer zum Büschenfelde K.-H.
        • et al.
        Interleukin-10 expression is autoregulated at the transcriptional level in human and murine kupffer cells.
        Hepatology. 1998; 27: 93-99
        • You Q.
        • Cheng L.
        • Kedl R.M.
        • Ju C.
        Mechanism of T cell tolerance induction by murine hepatic Kupffer cells.
        Hepatology. 2008; 48: 978-990
        • Carambia A.
        • Freund B.
        • Schwinge D.
        • Heine M.
        • Laschtowitz A.
        • Huber S.
        • et al.
        TGF-β-dependent induction of CD4+CD25+Foxp3+ Tregs by liver sinusoidal endothelial cells.
        J Hepatol. 2014; 61: 594-599
        • Warren A.
        • Le Couteur D.G.
        • Fraser R.
        • Bowen D.G.
        • McCaughan G.W.
        • Bertolino P.
        T lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells.
        Hepatology. 2006; 44: 1182-1190
        • Chen M.
        • Tabaczewski P.
        • Truscott S.M.
        • Van Kaer L.
        • Stroynowski I.
        Hepatocytes express abundant surface class I MHC and efficiently use transporter associated with antigen processing, tapasin, and low molecular weight polypeptide proteasome subunit components of antigen processing and presentation pathway.
        J Immunol. 2005; 175: 1047-1055
        • Bumgardner G.L.
        • Matas A.J.
        • Chen S.
        • Cahill D.
        • Cunningham T.R.
        • Payne W.D.
        • et al.
        Comparison of in vivo and in vitro immune response to purified hepatocytes.
        Transplantation. 1990; 49: 429-435
        • Bumgardner G.L.
        • Li J.
        • Apte S.
        • Heininger M.
        • Frankel W.L.
        Effect of tumor necrosis factor α and intercellular adhesion molecule-1 expression on immunogenicity of murine liver cells in mice.
        Hepatology. 1998; 28: 466-474
        • Bertolino P.
        • Heath W.R.
        • Hardy C.L.
        • Morahan G.
        • Miller J.F.A.P.
        Peripheral deletion of autoreactive CD8+ T cells in transgenic mice expressing H-2Kb in the liver.
        Eur J Immunol. 1995; 25: 1932-1942
        • Bowen D.G.
        • Zen M.
        • Holz L.
        • Davis T.
        • McCaughan G.W.
        • Bertolino P.
        The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity.
        J Clin Invest. 2004; 114: 701-712
        • Voehringer D.
        • Blaser C.
        • Grawitz A.B.
        • Chisari F.V.
        • Buerki K.
        • Pircher H.
        Break of T cell ignorance to a viral antigen in the liver induces hepatitis.
        J Immunol. 2000; 165: 2415-2422
        • Claassen M.A.A.
        • de Knegt R.J.
        • Tilanus H.W.
        • Janssen H.L.A.
        • Boonstra A.
        Abundant numbers of regulatory T cells localize to the liver of chronic hepatitis C infected patients and limit the extent of fibrosis.
        J Hepatol. 2010; 52: 315-321
        • Isogawa M.
        • Chung J.
        • Murata Y.
        • Kakimi K.
        • Chisari F.V.
        CD40 activation rescues antiviral CD8+ T cells from PD-1-mediated exhaustion.
        PLoS Pathog. 2013; 9: e1003490
        • Wohlleber D.
        • Kashkar H.
        • Gärtner K.
        • Frings Marianne K.
        • Odenthal M.
        • Hegenbarth S.
        • et al.
        TNF-induced target cell killing by CTL activated through cross-presentation.
        Cell Rep. 2012; 2: 478-487
        • Limmer A.
        • Ohl J.
        • Kurts C.
        • Ljunggren H.-G.
        • Reiss Y.
        • Groettrup M.
        • et al.
        Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T-cell tolerance.
        Nat Med. 2000; 6: 1348-1354
        • Höchst B.
        • Schildberg F.A.
        • Böttcher J.
        • Metzger C.
        • Huss S.
        • Türler A.
        • et al.
        Liver sinusoidal endothelial cells contribute to CD8 T cell tolerance toward circulating carcinoembryonic antigen in mice.
        Hepatology. 2012; 56: 1924-1933
        • Witmer-Pack M.D.
        • Crowley M.T.
        • Inaba K.
        • Steinman R.M.
        Macrophages, but not dendritic cells, accumulate colloidal carbon following administration in situ.
        J Cell Sci. 1993; 105: 965-973
        • Woo J.
        • Lu L.
        • Rao A.S.
        • Li Y.
        • Subbotin V.
        • Starzl T.E.
        • et al.
        Isolation, phenotype, and allostimulatory activity of mouse liver dendritic cells.
        Transplantation. 1994; 58: 484-491
        • O’Connell P.J.
        • Morelli A.E.
        • Logar A.J.
        • Thomson A.W.
        Phenotypic and functional characterization of mouse hepatic CD8α+ lymphoid-related dendritic cells.
        J Immunol. 2000; 165: 795-803
        • Benseler V.
        • Warren A.
        • Vo M.
        • Holz L.E.
        • Tay S.S.
        • Le Couteur D.G.
        • et al.
        Hepatocyte entry leads to degradation of autoreactive CD8 T cells.
        Proc Natl Acad Sci U S A. 2011; 108: 16735-16740
        • Tsukahara A.
        • Seki S.
        • Iiai T.
        • Moroda T.
        • Watanabe H.
        • Suzuki S.
        • et al.
        Mouse liver T cells: their change with aging and in comparison with peripheral T cells.
        Hepatology. 1997; 26: 301-309
        • Eberl G.
        • Lees R.
        • Smiley S.T.
        • Taniguchi M.
        • Grusby M.J.
        • MacDonald H.R.
        Tissue-specific segregation of CD1d-dependent and CD1d-independent NK T cells.
        J Immunol. 1999; 162: 6410-6419
        • Xu D.
        • Fu J.
        • Jin L.
        • Zhang H.
        • Zhou C.
        • Zou Z.
        • et al.
        Circulating and liver resident CD4+CD25+ regulatory T cells actively influence the antiviral immune response and disease progression in patients with hepatitis B.
        J Immunol. 2006; 177: 739-747
        • Oo Y.H.
        • Weston C.J.
        • Lalor P.F.
        • Curbishley S.M.
        • Withers D.R.
        • Reynolds G.M.
        • et al.
        Distinct roles for CCR4 and CXCR3 in the recruitment and positioning of regulatory T cells in the inflamed human liver.
        J Immunol. 2010; 184: 2886-2898
        • Sonoda K.-H.
        • Faunce D.E.
        • Taniguchi M.
        • Exley M.
        • Balk S.
        • Stein-Streilein J.
        NK T cell-derived IL-10 is essential for the differentiation of antigen-specific T regulatory cells in systemic tolerance.
        J Immunol. 2001; 166: 42-50
        • Jinushi M.
        • Takehara T.
        • Tatsumi T.
        • Yamaguchi S.
        • Sakamori R.
        • Hiramatsu N.
        • et al.
        Natural killer cell and hepatic cell interaction via NKG2A leads to dendritic cell-mediated induction of CD4+ CD25+ T cells with PD-1-dependent regulatory activities.
        Immunology. 2007; 120: 73-82
        • Stross L.
        • Günther J.
        • Gasteiger G.
        • Asen T.
        • Graf S.
        • Aichler M.
        • et al.
        Foxp3+ regulatory T cells protect the liver from immune damage and compromise virus control during acute experimental hepatitis B virus infection in mice.
        Hepatology. 2012; 56: 873-883
        • Lechner F.
        • Gruener N.H.
        • Urbani S.
        • Uggeri J.
        • Santantonio T.
        • Kammer A.R.
        • et al.
        CD8+ T lymphocyte responses are induced during acute hepatitis C virus infection but are not sustained.
        Eur J Immunol. 2000; 30: 2479-2487
        • Lechner F.
        • Wong D.K.H.
        • Dunbar P.R.
        • Chapman R.
        • Chung R.T.
        • Dohrenwend P.
        • et al.
        Analysis of successful immune responses in persons infected with hepatitis C virus.
        J Exp Med. 2000; 191: 1499-1512
        • Webster G.J.M.
        • Reignat S.
        • Maini M.K.
        • Whalley S.A.
        • Ogg G.S.
        • King A.
        • et al.
        Incubation phase of acute hepatitis B in man: dynamic of cellular immune mechanisms.
        Hepatology. 2000; 32: 1117-1124
        • Thimme R.
        • Oldach D.
        • Chang K.-M.
        • Steiger C.
        • Ray S.C.
        • Chisari F.V.
        Determinants of viral clearance and persistence during acute hepatitis C virus infection.
        J Exp Med. 2001; 194: 1395-1406
        • Maini M.K.
        • Boni C.
        • Lee C.K.
        • Larrubia J.R.
        • Reignat S.
        • Ogg G.S.
        • et al.
        The role of virus-specific CD8+ cells in liver damage and viral control during persistent hepatitis B virus infection.
        J Exp Med. 2000; 191: 1269-1280
        • Lang K.S.
        • Georgiev P.
        • Recher M.
        • Navarini A.A.
        • Bergthaler A.
        • Heikenwalder M.
        • et al.
        Immunoprivileged status of the liver is controlled by Toll-like receptor 3 signaling.
        J Clin Invest. 2006; 116: 2456-2463
        • Béland K.
        • Lapierre P.
        • Djilali-Saiah I.
        • Alvarez F.
        Liver restores immune homeostasis after local inflammation despite the presence of autoreactive T cells.
        PLoS One. 2012; 7: e48192
        • Hennessy E.J.
        • Parker A.E.
        • O’Neill L.A.J.
        Targeting Toll-like receptors: emerging therapeutics?.
        Nat Rev Drug Discov. 2010; 9: 293-307
        • Wuensch S.A.
        • Spahn J.
        • Crispe I.N.
        Direct, help-independent priming of CD8+ T cells by adeno-associated virus–transduced hepatocytes.
        Hepatology. 2010; 52: 1068-1077
        • Spahn J.
        • Pierce R.H.
        • Crispe I.N.
        Ineffective CD8+ T-cell immunity to adeno-associated virus can result in prolonged liver injury and fibrogenesis.
        Am J Pathol. 2011; 179: 2370-2381
        • Tay S.S.
        • Wong Y.C.
        • McDonald D.M.
        • Wood N.A.W.
        • Roediger B.
        • Sierro F.
        • et al.
        Antigen expression level threshold tunes the fate of CD8 T cells during primary hepatic immune responses.
        Proc Natl Acad Sci U S A. 2014; 111: E2540-E2549
        • Matloubian M.
        • Kolhekar S.R.
        • Somasundaram T.
        • Ahmed R.
        Molecular determinants of macrophage tropism and viral persistence: importance of single amino acid changes in the polymerase and glycoprotein of lymphocytic choriomeningitis virus.
        J Virol. 1993; 67: 7340-7349
        • Borrow P.
        • Evans C.F.
        • Oldstone M.B.
        Virus-induced immunosuppression: immune system-mediated destruction of virus-infected dendritic cells results in generalized immune suppression.
        J Virol. 1995; 69: 1059-1070
        • Wherry E.J.
        • Blattman J.N.
        • Murali-Krishna K.
        • van der Most R.
        • Ahmed R.
        Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment.
        J Virol. 2003; 77: 4911-4927
        • Moskophidis D.
        • Lechner F.
        • Pircher H.
        • Zinkernagel R.M.
        Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells.
        Nature. 1993; 362: 758-761
        • Barber D.L.
        • Wherry E.J.
        • Masopust D.
        • Zhu B.
        • Allison J.P.
        • Sharpe A.H.
        • et al.
        Restoring function in exhausted CD8 T cells during chronic viral infection.
        Nature. 2006; 439: 682-687
        • Jin H.-T.
        • Anderson A.C.
        • Tan W.G.
        • West E.E.
        • Ha S.-J.
        • Araki K.
        • et al.
        Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection.
        Proc Natl Acad Sci U S A. 2010; 107: 14733-14738
        • Blackburn S.D.
        • Shin H.
        • Haining W.N.
        • Zou T.
        • Workman C.J.
        • Polley A.
        • et al.
        Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection.
        Nat Immunol. 2009; 10: 29-37
        • Brooks D.G.
        • Trifilo M.J.
        • Edelmann K.H.
        • Teyton L.
        • McGavern D.B.
        • Oldstone M.B.A.
        Interleukin-10 determines viral clearance or persistence in vivo.
        Nat Med. 2006; 12: 1301-1309
        • Ejrnaes M.
        • Filippi C.M.
        • Martinic M.M.
        • Ling E.M.
        • Togher L.M.
        • Crotty S.
        • et al.
        Resolution of a chronic viral infection after interleukin-10 receptor blockade.
        J Exp Med. 2006; 203: 2461-2472
        • Penaloza-MacMaster P.
        • Kamphorst A.O.
        • Wieland A.
        • Araki K.
        • Iyer S.S.
        • West E.E.
        • et al.
        Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection.
        J Exp Med. 2014; 211: 1905-1918
        • Schmitz I.
        • Schneider C.
        • Fröhlich A.
        • Frebel H.
        • Christ D.
        • Leonard W.J.
        • et al.
        IL-21 restricts virus-driven Treg cell expansion in chronic LCMV infection.
        PLoS Pathog. 2013; 9: e1003362
        • Waggoner S.N.
        • Cornberg M.
        • Selin L.K.
        • Welsh R.M.
        Natural killer cells act as rheostats modulating antiviral T cells.
        Nature. 2012; 481: 394-398
        • Lang P.A.
        • Lang K.S.
        • Xu H.C.
        • Grusdat M.
        • Parish I.A.
        • Recher M.
        • et al.
        Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8+ T-cell immunity.
        Proc Natl Acad Sci U S A. 2012; 109: 1210-1215
        • Cook K.D.
        • Whitmire J.K.
        The depletion of NK cells prevents T cell exhaustion to efficiently control disseminating virus infection.
        J Immunol. 2013; 190: 641-649
        • Chen J.
        • Wang X.-M.
        • Wu X.-J.
        • Wang Y.
        • Zhao H.
        • Shen B.
        • et al.
        Intrahepatic levels of PD-1/PD-L correlate with liver inflammation in chronic hepatitis B.
        Inflamm Res. 2011; 60: 47-53
        • Mengshol J.A.
        • Golden-Mason L.
        • Arikawa T.
        • Smith M.
        • Niki T.
        • McWilliams R.
        • et al.
        A Crucial role for Kupffer cell-derived galectin-9 in regulation of T cell immunity in hepatitis C infection.
        PLoS One. 2010; 5: e9504
        • Flynn J.K.
        • Dore G.J.
        • Hellard M.
        • Yeung B.
        • Rawlinson W.D.
        • White P.A.
        • et al.
        Early IL-10 predominant responses are associated with progression to chronic hepatitis C virus infection in injecting drug users.
        J Viral Hepat. 2011; 18: 549-561
        • Li J.
        • Wu W.
        • Peng G.
        • Chen F.
        • Bai M.
        • Zheng M.
        • et al.
        HBcAg induces interleukin-10 production, inhibiting HBcAg-specific Th17 responses in chronic hepatitis B patients.
        Immunol Cell Biol. 2010; 88: 834-841
        • Stoop J.N.
        • van der Molen R.G.
        • Baan C.C.
        • van der Laan L.J.W.
        • Kuipers E.J.
        • Kusters J.G.
        • et al.
        Regulatory T cells contribute to the impaired immune response in patients with chronic hepatitis B virus infection.
        Hepatology. 2005; 41: 771-778
        • Peppa D.
        • Gill U.S.
        • Reynolds G.
        • Easom N.J.W.
        • Pallett L.J.
        • Schurich A.
        • et al.
        Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell–mediated deletion.
        J Exp Med. 2013; 210: 99-114
        • Mueller S.N.
        • Ahmed R.
        High antigen levels are the cause of T cell exhaustion during chronic viral infection.
        Proc Natl Acad Sci U S A. 2009; 106: 8623-8628
        • Richter K.
        • Brocker T.
        • Oxenius A.
        Antigen amount dictates CD8+ T-cell exhaustion during chronic viral infection irrespective of the type of antigen presenting cell.
        Eur J Immunol. 2012; 42: 2290-2304
        • Bucks C.M.
        • Norton J.A.
        • Boesteanu A.C.
        • Mueller Y.M.
        • Katsikis P.D.
        Chronic antigen stimulation alone is sufficient to drive CD8+ T cell exhaustion.
        J Immunol. 2009; 182: 6697-6708
        • Zaiss A.-K.
        • Liu Q.
        • Bowen G.P.
        • Wong N.C.W.
        • Bartlett J.S.
        • Muruve D.A.
        Differential activation of innate immune responses by adenovirus and adeno-associated virus vectors.
        J Virol. 2002; 76: 4580-4590
        • Cunningham E.C.
        • Tay S.S.
        • Wang C.
        • Rtshiladze M.
        • Wang Z.Z.
        • McGuffog C.
        • et al.
        Gene therapy for tolerance: high-level expression of donor major histocompatibility complex in the liver overcomes naive and memory alloresponses to skin grafts.
        Transplantation. 2013; 95: 70-77
        • Isogawa M.
        • Furuichi Y.
        • Chisari F.V.
        Oscillating CD8+ T cell effector functions after antigen recognition in the liver.
        Immunity. 2005; 23: 53-63
        • Prato S.
        • Zhan Y.
        • Mintern J.D.
        • Villadangos J.A.
        Rapid deletion and inactivation of CTLs upon recognition of a number of target cells over a critical threshold.
        J Immunol. 2013; 191: 3534-3544
        • Fuller M.J.
        • Callendret B.
        • Zhu B.
        • Freeman G.J.
        • Hasselschwert D.L.
        • Satterfield W.
        • et al.
        Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1).
        Proc Natl Acad Sci U S A. 2013; 110: 15001-15006
        • Das A.
        • Ellis G.
        • Pallant C.
        • Lopes A.R.
        • Khanna P.
        • Peppa D.
        • et al.
        IL-10–producing regulatory B cells in the pathogenesis of chronic hepatitis B virus infection.
        J Immunol. 2012; 189: 3925-3935
        • Schurich A.
        • Khanna P.
        • Lopes A.R.
        • Han K.J.
        • Peppa D.
        • Micco L.
        • et al.
        Role of the coinhibitory receptor cytotoxic T lymphocyte antigen-4 on apoptosis-prone CD8 T cells in persistent hepatitis B virus infection.
        Hepatology. 2011; 53: 1494-1503
        • Fisicaro P.
        • Valdatta C.
        • Massari M.
        • Loggi E.
        • Ravanetti L.
        • Urbani S.
        • et al.
        Combined blockade of programmed death-1 and activation of CD137 increase responses of human liver T cells against HBV, but not HCV.
        Gastroenterology. 2012; 143: 1576-1585
        • Nakamoto N.
        • Cho H.
        • Shaked A.
        • Olthoff K.
        • Valiga M.E.
        • Kaminski M.
        • et al.
        Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade.
        PLoS Pathog. 2009; 5: e1000313
        • Nakamoto N.
        • Kaplan D.E.
        • Coleclough J.
        • Li Y.
        • Valiga M.E.
        • Kaminski M.
        • et al.
        Functional restoration of HCV-specific CD8 T cells by PD-1 blockade is defined by PD-1 expression and compartmentalization.
        Gastroenterology. 2008; 134: 1927-1937
        • Owusu Sekyere S.
        • Suneetha P.V.
        • Kraft A.R.M.
        • Zhang S.
        • Dietz J.
        • Sarrazin C.
        • et al.
        A heterogeneous hierarchy of co-regulatory receptors regulates exhaustion of HCV-specific CD8 T cells in patients with chronic hepatitis C.
        J Hepatol. 2015; 62: 31-40
        • Blackburn S.D.
        • Shin H.
        • Freeman G.J.
        • Wherry E.J.
        Selective expansion of a subset of exhausted CD8 T cells by αPD-L1 blockade.
        Proc Natl Acad Sci U S A. 2008; 105: 15016-15021
        • Velu V.
        • Titanji K.
        • Zhu B.
        • Husain S.
        • Pladevega A.
        • Lai L.
        • et al.
        Enhancing SIV-specific immunity in vivo by PD-1 blockade.
        Nature. 2009; 458: 206-210
        • Gardiner D.
        • Lalezari J.
        • Lawitz E.
        • DiMicco M.
        • Ghalib R.
        • Reddy K.R.
        • et al.
        A randomized, double-blind, placebo-controlled assessment of BMS-936558, a fully human monoclonal antibody to programmed death-1 (PD-1), in patients with chronic hepatitis C virus infection.
        PLoS One. 2013; 8: e63818
        • Schurich A.
        • Pallett L.J.
        • Lubowiecki M.
        • Singh H.D.
        • Gill U.S.
        • Kennedy P.T.
        • et al.
        The third signal cytokine IL-12 rescues the anti-viral function of exhausted HBV-specific CD8 T cells.
        PLoS Pathog. 2013; 9: e1003208
        • Kurktschiev P.D.
        • Raziorrouh B.
        • Schraut W.
        • Backmund M.
        • Wächtler M.
        • Wendtner C.-M.
        • et al.
        Dysfunctional CD8+ T cells in hepatitis B and C are characterized by a lack of antigen-specific T-bet induction.
        J Exp Med. 2014; 211: 2047-2059
        • Battegay M.
        • Moskophidis D.
        • Rahemtulla A.
        • Hengartner H.
        • Mak T.W.
        • Zinkernagel R.M.
        Enhanced establishment of a virus carrier state in adult CD4+ T-cell-deficient mice.
        J Virol. 1994; 68: 4700-4704
        • Matloubian M.
        • Concepcion R.J.
        • Ahmed R.
        CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection.
        J Virol. 1994; 68: 8056-8063
        • Zajac A.J.
        • Blattman J.N.
        • Murali-Krishna K.
        • Sourdive D.J.D.
        • Suresh M.
        • Altman J.D.
        • et al.
        Viral immune evasion due to persistence of activated T cells without effector function.
        J Exp Med. 1998; 188: 2205-2213
        • Aubert R.D.
        • Kamphorst A.O.
        • Sarkar S.
        • Vezys V.
        • Ha S.-J.
        • Barber D.L.
        • et al.
        Antigen-specific CD4 T-cell help rescues exhausted CD8 T cells during chronic viral infection.
        Proc Natl Acad Sci U S A. 2011; 108: 21182-21187
        • Elsaesser H.
        • Sauer K.
        • Brooks D.G.
        IL-21 is required to control chronic viral infection.
        Science. 2009; 324: 1569-1572
        • Fröhlich A.
        • Kisielow J.
        • Schmitz I.
        • Freigang S.
        • Shamshiev A.T.
        • Weber J.
        • et al.
        IL-21R on T cells Is critical for sustained functionality and control of chronic viral infection.
        Science. 2009; 324: 1576-1580
        • Yi J.S.
        • Du M.
        • Zajac A.J.
        A vital role for interleukin-21 in the control of a chronic viral infection.
        Science. 2009; 324: 1572-1576
        • Derkow K.
        • Müller A.
        • Eickmeier I.
        • Seidel D.
        • Rust Moreira M.V.
        • Kruse N.
        • et al.
        Failure of CD4 T-cells to respond to liver-derived antigen and to provide help to CD8 T-cells.
        PLoS One. 2011; 6: e21847
        • Tay S.S.
        • Wong Y.C.
        • Roediger B.
        • Sierro F.
        • Lu B.
        • McDonald D.M.
        • et al.
        Intrahepatic activation of naive CD4+ T cells by liver-resident phagocytic cells.
        J Immunol. 2014; 193: 2087-2095
        • Grakoui A.
        • Shoukry N.H.
        • Woollard D.J.
        • Han J.-H.
        • Hanson H.L.
        • Ghrayeb J.
        • et al.
        HCV persistence and immune evasion in the absence of memory T cell help.
        Science. 2003; 302: 659-662
        • Asabe S.
        • Wieland S.F.
        • Chattopadhyay P.K.
        • Roederer M.
        • Engle R.E.
        • Purcell R.H.
        • et al.
        The size of the viral inoculum contributes to the outcome of hepatitis B virus infection.
        J Virol. 2009; 83: 9652-9662