Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 213, Issue 6, Pages 1079-1093Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20151218
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Funding
- National Natural Science Foundation of China [31390433, 91429303]
- Chinese Ministry of Science and Technology (973 Basic Science Project) [2012CB519004, 2013CB944900]
- Chinese Academy of Sciences Key Project [KJZD-EW-L10-003]
- National Science and Technology Major Projects [2013ZX10002002]
- Chongqing Science and Technology Department (Basic Science Project) [cstc2013jcyjC10002]
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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-gamma (IFN-gamma) 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-gamma production. IFN-gamma 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-gamma during viral persistence in the liver, providing new mechanistic insights regarding the maintenance of systemic antigen-specific tolerance during HBV persistence.
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