title: Interferon-γ facilitates hepatic antiviral T cell retention for the maintenance of liver-induced systemic tolerance.
abstract: Persistent exposure to liver pathogens leads to systemic antigen-specific tolerance, a major cause of chronicity during hepatotropic infection. The mechanism regarding how this systemic tolerance is maintained remains poorly elucidated. In a well established mouse model of hepatitis B virus (HBV) persistence-induced systemic tolerance, we observed that interferon-γ (IFN-γ) deficiency led to complete loss of tolerance, resulting in robust anti-HBV responses upon peripheral vaccination. The recovery of vaccine-induced anti-HBV responses was mainly caused by the retained antigen-specific CD4(+) T cells rather than decreased functional inhibitory cells in the periphery. Mechanistically, HBV persistence induced sustained hepatic CD4(+) T cell-derived IFN-γ production. IFN-γ was found to promote CXCL9 secretion from liver-resident macrophages. This T cell chemokine facilitated the retention of antiviral CD4(+) T cells in the liver in a CXCR3-dependent manner. Hepatic sequestrated antiviral CD4(+) T cells subsequently underwent local apoptotic elimination partially via cytotoxic T lymphocyte-associated protein 4 ligation. These findings reveal an unexpected tolerogenic role for IFN-γ during viral persistence in the liver, providing new mechanistic insights regarding the maintenance of systemic antigen-specific tolerance during HBV persistence.
authors.affiliation: Institute of Immunology and the Key Laboratory of Innate Immunity and Chronic Disease, Chinese Academy of Science, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Zhutian
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Institute of Immunology and the Key Laboratory of Innate Immunity and Chronic Disease, Chinese Academy of Science, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China Hefei National Laboratory for Physical Sciences at the Microscale, Hefei 230027, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Li
authors.affiliation: Institute of Immunology and the Key Laboratory of Innate Immunity and Chronic Disease, Chinese Academy of Science, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Yongyan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Institute of Immunology and the Key Laboratory of Innate Immunity and Chronic Disease, Chinese Academy of Science, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Haiming
authors.initials: H
authors.lastname: Wei
authors.affiliation: Institute of Immunology and the Key Laboratory of Innate Immunity and Chronic Disease, Chinese Academy of Science, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Sun
authors.affiliation: Institute of Immunology and the Key Laboratory of Innate Immunity and Chronic Disease, Chinese Academy of Science, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei 230027, China Hefei National Laboratory for Physical Sciences at the Microscale, Hefei 230027, China Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China tzg@ustc.edu.cn.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Tian
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D054370:Chemokine CXCL9 / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D006509:Hepatitis B / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology; D006515:Hepatitis B virus / Q000276:immunology*; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D008099:Liver / Q000276:immunology* / Q000821:virology; D008297:Male; D051379:Mice; D018345:Mice, Knockout
chemical_list: D054370:Chemokine CXCL9; C485969:Cxcl9 protein, mouse; C000611649:IFNG protein, mouse; D007371:Interferon-gamma