title: Expression of Viral Antigen by the Liver Leads to Chronic Infection Through the Generation of Regulatory T Cells.
abstract: OBJECTIVE
  The constant exposure of the liver to food and bacterial antigens through the mesenteric circulation requires it to maintain tolerance while preserving the ability to mount an effective immune response against pathogens. We investigated the contribution of the liver's tolerogenic nature on the establishment of chronic viral infections.
  
  
  METHODS
  TTR-NP mice, which express the nucleoprotein (NP) of lymphocytic choriomeningitis virus (LCMV) specifically in hepatocytes under control of a modified transthyretin (TTR) promoter, were infected with the Armstrong (Arm) or WE acute strains of LCMV.
  
  
  RESULTS
  The infection persisted for at least 147 days in TTR-NP mice. Expression of NP by the liver induced a strong peripheral tolerance against NP that was mediated by interleukin-10-secreting CD4+regulatory T cells, leading to high PD-1 (programmed death-1) expression and reduced effector function of virus-specific T cells. Despite an active immune response against LCMV, peripheral tolerance against a single viral protein was sufficient to induce T-cell exhaustion and chronic LCMV Armstrong (Arm) or WE infection by limiting the antiviral T-cell response in an otherwise immunocompetent host. Regulatory T-cell depletion of chronically infected TTR-NP mice led to functional restoration of LCMV-specific CD4+and CD8+T cell responses and viral clearance.
  
  
  CONCLUSIONS
  Expression of a viral antigen by hepatocytes can induce a state of peripheral tolerance mediated by regulatory T cells that can lead to the establishment of a chronic viral infection. Strategies targeting regulatory T cells in patients chronically infected with hepatotropic viruses could represent a promising approach to restore functional antiviral immunity and clear infection.
authors.affiliation: Immunovirology laboratory, Institut national de la recherche scientifique, INRS-Institut Armand-Frappier, Laval, Quebec, Canada.
authors.forename: Pascal
authors.initials: P
authors.lastname: Lapierre
authors.affiliation: Immunovirology laboratory, Institut national de la recherche scientifique, INRS-Institut Armand-Frappier, Laval, Quebec, Canada.
authors.forename: Valérie
authors.initials: V
authors.lastname: Janelle
authors.affiliation: Immunovirology laboratory, Institut national de la recherche scientifique, INRS-Institut Armand-Frappier, Laval, Quebec, Canada.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Langlois
authors.affiliation: Immunovirology laboratory, Institut national de la recherche scientifique, INRS-Institut Armand-Frappier, Laval, Quebec, Canada.
authors.forename: Esther
authors.initials: E
authors.lastname: Tarrab
authors.affiliation: Immunovirology laboratory, Institut national de la recherche scientifique, INRS-Institut Armand-Frappier, Laval, Quebec, Canada.
authors.forename: Tania
authors.initials: T
authors.lastname: Charpentier
authors.affiliation: Immunovirology laboratory, Institut national de la recherche scientifique, INRS-Institut Armand-Frappier, Laval, Quebec, Canada.
authors.forename: Alain
authors.initials: A
authors.lastname: Lamarre
keywords: ALT, alanine aminotransferase; APC, allophycocyanin; Arm, Armstrong strain; BTLA, B and T lymphocyte attenuator; CFSE, carboxyfluorescein diacetate succinimidyl ester; CTL, cytotoxic T lymphocyte; Chronic Infection; ELISA, enzyme-linked immunoassay; FACS, fluorescence-activated cell sorter; FoxP3, forkhead box P3; GP, glycoprotein; HBV, hepatitis B virus; HCV, hepatitis C virus; Hepatitis; IFN, interferon; IL, interleukin; IP, intraperitoneal; IV, intravenous; LCMV, lymphocytic choriomeningitis virus; LIL, liver-infiltrating lymphocytes; NP, nucleoprotein; P14, GP33–41-specific TCR transgenic; PD-1, programmed death-1; PD-L1, programmed death-ligand-1; PE, phycoerythrin; RAG, recombination-activating gene; TCR, T-cell receptor; TNF-α, tumor necrosis factor-α; TNP4, NP396–404-specific TCR transgenic; TTR, transthyretin; Tolerance; Treg, regulatory T cell; pfu, plaque-forming units