title: Negative regulation of type I IFN expression by OASL1 permits chronic viral infection and CD8⁺ T-cell exhaustion.
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.
authors.affiliation: Genome Research Center, Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors.forename: Myeong Sup
authors.initials: MS
authors.lastname: Lee
authors.forename: Chan Hee
authors.initials: CH
authors.lastname: Park
authors.forename: Yun Hee
authors.initials: YH
authors.lastname: Jeong
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Kim
authors.forename: Sang-Jun
authors.initials: SJ
authors.lastname: Ha
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D060467:Disease Resistance; D015536:Down-Regulation; D005260:Female; D007113:Immunity, Innate; D050839:Interferon Regulatory Factor-7 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D007370:Interferon Type I / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008216:Lymphocytic Choriomeningitis / Q000097:blood / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014766:Viremia / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000821:virology
chemical_list: C508032:Ifnar1 protein, mouse; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; C494235:Irf7 protein, mouse; D053633:Receptor, Interferon alpha-beta; C475083:Oasl1 protein, mouse; D015088:2',5'-Oligoadenylate Synthetase