Expression of Viral Antigen by the Liver Leads to Chronic Infection Through the Generation of Regulatory T CellsReportar como inadecuado

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1 INRS-IAF - Institut Armand Frappier

Abstract : 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+ Tcell responses and viral clearance. Conclusions: Expression of a viral antigen by hepatocytes can induce a state of peripheral tolerance mediated by regulatory Tcells 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.

Keywords : Chronic Infection Hepatitis Tolerance

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



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