Abstract
The type I interferons (IFN-Is) are critical not only in early viral control but also in prolonged T-cell immune responses. However, chronic viral infections such as those of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) in humans and lymphocytic choriomeningitis virus (LCMV) in mice overcome this early IFN-I barrier and induce viral persistence and exhaustion of T-cell function. Although various T-cell-intrinsic and -extrinsic factors are known to contribute to induction of chronic conditions, the roles of IFN-I negative regulators in chronic viral infections have been largely unexplored. Herein, we explored whether 2'-5' oligoadenylate synthetase-like 1 (OASL1), a recently defined IFN-I negative regulator, plays a key role in the virus-specific T-cell response and viral defense against chronic LCMV. To this end, we infected Oasl1 knockout and wild-type mice with LCMV CL-13 (a chronic virus) and monitored T-cell responses, serum cytokine levels, and viral titers. LCMV CL-13-infected Oasl1 KO mice displayed a sustained level of serum IFN-I, which was primarily produced by splenic plasmacytoid dendritic cells, during the very early phase of infection (2-3 days post-infection). Oasl1 deficiency also led to the accelerated elimination of viremia and induction of a functional antiviral CD8 T-cell response, which critically depended on IFN-I receptor signaling. Together, these results demonstrate that OASL1-mediated negative regulation of IFN-I production at an early phase of infection permits viral persistence and suppresses T-cell function, suggesting that IFN-I negative regulators, including OASL1, could be exciting new targets for preventing chronic viral infection.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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2',5'-Oligoadenylate Synthetase / biosynthesis
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2',5'-Oligoadenylate Synthetase / genetics
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2',5'-Oligoadenylate Synthetase / metabolism*
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Animals
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / virology
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Dendritic Cells / immunology
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Dendritic Cells / metabolism
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Dendritic Cells / virology
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Disease Resistance
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Down-Regulation*
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Female
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Immunity, Innate
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Interferon Regulatory Factor-7 / biosynthesis
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Interferon Regulatory Factor-7 / genetics
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Interferon Regulatory Factor-7 / metabolism
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Interferon Type I / blood
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Interferon Type I / genetics
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Interferon Type I / metabolism*
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Lymphocytic Choriomeningitis / blood
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Lymphocytic Choriomeningitis / immunology*
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Lymphocytic Choriomeningitis / metabolism
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Lymphocytic Choriomeningitis / virology
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Lymphocytic choriomeningitis virus / immunology*
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Macrophages / immunology
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Macrophages / metabolism
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Macrophages / virology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Receptor, Interferon alpha-beta / antagonists & inhibitors
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Receptor, Interferon alpha-beta / genetics
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Receptor, Interferon alpha-beta / metabolism*
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Signal Transduction
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Viremia / blood
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Viremia / immunology
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Viremia / metabolism
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Viremia / virology
Substances
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Ifnar1 protein, mouse
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Interferon Regulatory Factor-7
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Interferon Type I
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Irf7 protein, mouse
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Receptor, Interferon alpha-beta
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Oasl1 protein, mouse
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2',5'-Oligoadenylate Synthetase
Grants and funding
This work was supported by the Global Research Laboratory (GRL) program (K20704000006-10A0500-00610 to YJK), World Class University (WCU) program (R312010000100860 to YJK), Basic Science and Research Program (2009-0077426, 2010-0004892, and 2010-0027222 to SJH), National Nuclear R&D Program (2010-0018544 to SJH), and Bio & Medical Technology Development Program (2012M3A9B4028264 to YJK and SJH) of the National Research Foundation (NRF) funded by the Korean government (MEST). This work was also supported by a grant of the Korean Health Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A101750 to S.J.H.). We are also grateful for support by a TJ Park Junior Faculty Fellowship from the POSCO TJ Park Foundation, Republic of Korea. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.