Expression of Viral Antigen by the Liver Leads to Chronic Infection Through the Generation of Regulatory T Cells.

Pascal Lapierre,Valérie Janelle,Marie-Pierre Langlois,Tania Charpentier,Alain Lamarre,Esther Tarrab

doi:10.1016/j.jcmgh.2015.02.002

Abstract

Background & AimsThe 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.MethodsTTR-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.ResultsThe 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.ConclusionsExpression 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.

Highlights

BACKGROUND & AIMSThe 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
Expression of NP by the liver induced a strong peripheral tolerance against NP that was mediated by interleukin-10-secreting CD4þ regulatory T cells, leading to high programmed death-1 (PD-1) expression and reduced effector function of virus-specific T cells
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

Summary

Methods

TTR-NP mice, which express the nucleoprotein (NP) of lymphocytic choriomeningitis virus (LCMV) in hepatocytes under control of a modified transthyretin (TTR) promoter, were infected with the Armstrong (Arm) or WE acute strains of LCMV. Transthyretin-nucleoprotein (TTR-NP) transgenic mice[8] (8- to 12-week-old females) expressing LCMV NP in hepatocytes CHU Sainte-Justine, Montreal, Canada) or control C57BL/6 (B6) mice (8- to 12-week-old females) (Charles River, Montreal, Canada) were infected with either acute strains LCMV-Arm (200 plaque-forming units [pfu] intraperitoneally [IP]) or LCMV-WE (200 pfu intravenously [IV]). The glycoprotein GP33–41-specific TCR transgenic P14 mice were kindly provided by P. The recombination-activating gene–nucleoprotein (RAG-NP) mice were obtained by crossing TTR-NP and RAG-1 mice (kindly provided by C Daniel, INRSInstitut Armand-Frappier, Laval, Quebec, Canada). The RAG-1 phenotype was assessed by flow cytometry, and NP expression was monitored by polymerase chain reaction, as previously described elsewhere.[8]

Results

Discussion

Conclusion