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Overwhelming antigen exposure can result in suboptimal CD8\n            <jats:sup>+<\/jats:sup>\n            T cell responses, leading to chronic infection. This altered CD8\n            <jats:sup>+<\/jats:sup>\n            T cell differentiation state, termed exhaustion, is characterized by reduced effector function, upregulation of inhibitory receptors, and altered expression of transcription factors. Prevention of overwhelming antigen exposure to limit CD8\n            <jats:sup>+<\/jats:sup>\n            T cell exhaustion is of significant interest for the control of chronic infection. The transcription factor interferon regulatory factor 9 (IRF9) is a component of type I interferon (IFN-I) signaling downstream of the IFN-I receptor (IFNAR). Using acute infection of mice with lymphocytic choriomeningitis virus (LCMV) strain Armstrong, we show here that IRF9 limited early LCMV replication by regulating expression of interferon-stimulated genes and IFN-I and by controlling levels of IRF7, a transcription factor essential for IFN-I production. Infection of IRF9- or IFNAR-deficient mice led to a loss of early restriction of viral replication and impaired antiviral responses in dendritic cells, resulting in CD8\n            <jats:sup>+<\/jats:sup>\n            T cell exhaustion and chronic infection. Differences in the antiviral activities of IRF9- and IFNAR-deficient mice and dendritic cells provided further evidence of IRF9-independent IFN-I signaling. Thus, our findings illustrate a CD8\n            <jats:sup>+<\/jats:sup>\n            T cell-extrinsic function for IRF9, as a signaling factor downstream of IFNAR, in preventing overwhelming antigen exposure resulting in CD8\n            <jats:sup>+<\/jats:sup>\n            T cell exhaustion and, ultimately, chronic infection.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            During early viral infection, overwhelming antigen exposure can cause functional exhaustion of CD8\n            <jats:sup>+<\/jats:sup>\n            T cells and lead to chronic infection. Here we show that the transcription factor interferon regulatory factor 9 (IRF9) plays a decisive role in preventing CD8\n            <jats:sup>+<\/jats:sup>\n            T cell exhaustion. Using acute infection of mice with LCMV strain Armstrong, we found that IRF9 limited early LCMV replication by regulating expression of interferon-stimulated genes and\n            <jats:italic>Irf7<\/jats:italic>\n            , encoding a transcription factor crucial for type I interferon (IFN-I) production, as well as by controlling the levels of IFN-I. Infection of IRF9-deficient mice led to a chronic infection that was accompanied by CD8\n            <jats:sup>+<\/jats:sup>\n            T cell exhaustion due to defects extrinsic to T cells. Our findings illustrate an essential role for IRF9, as a mediator downstream of IFNAR, in preventing overwhelming antigen exposure causing CD8\n            <jats:sup>+<\/jats:sup>\n            T cell exhaustion and leading to chronic viral infection.\n          <\/jats:p>","DOI":"10.1128\/jvi.01219-17","type":"journal-article","created":{"date-parts":[[2017,9,7]],"date-time":"2017-09-07T03:17:41Z","timestamp":1504754261000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":43,"title":["IRF9 Prevents CD8\n            <sup>+<\/sup>\n            T Cell Exhaustion in an Extrinsic Manner during Acute Lymphocytic Choriomeningitis Virus Infection"],"prefix":"10.1128","volume":"91","author":[{"given":"Magdalena","family":"Huber","sequence":"first","affiliation":[{"name":"Institute of Medical Microbiology and Hygiene, University of Marburg, Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara","family":"Suprunenko","sequence":"additional","affiliation":[{"name":"School of Life and Environmental Sciences, the Marie Bashir Institute for Infectious Diseases and Biosecurity, the Charles Perkins Centre, and the Bosch Institute, The University of Sydney, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Ashhurst","sequence":"additional","affiliation":[{"name":"Department of Pathology and the Bosch Institute, School of Medical Sciences, Sydney Medical School, University of Sydney, Sydney, Australia, and Sydney Cytometry Facility, The University of Sydney and the Centenary Institute, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Marbach","sequence":"additional","affiliation":[{"name":"Institute of Medical Microbiology and Hygiene, University of Marburg, Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hartmann","family":"Raifer","sequence":"additional","affiliation":[{"name":"Institute of Medical Microbiology and Hygiene, University of Marburg, Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svenja","family":"Wolff","sequence":"additional","affiliation":[{"name":"Institute of Virology, University of Marburg, Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Strecker","sequence":"additional","affiliation":[{"name":"Institute of Virology, University of Marburg, Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barney","family":"Viengkhou","sequence":"additional","affiliation":[{"name":"School of Life and Environmental Sciences, the Marie Bashir Institute for Infectious Diseases and Biosecurity, the Charles Perkins Centre, and the Bosch Institute, The University of Sydney, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"So Ri","family":"Jung","sequence":"additional","affiliation":[{"name":"School of Life and Environmental Sciences, the Marie Bashir Institute for Infectious Diseases and Biosecurity, the Charles Perkins Centre, and the Bosch Institute, The University of Sydney, Sydney, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah-Lena","family":"Obermann","sequence":"additional","affiliation":[{"name":"Institute of Immunology, University of Marburg, Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Bauer","sequence":"additional","affiliation":[{"name":"Institute of Immunology, University of Marburg, Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haifeng C.","family":"Xu","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine II, University of D\u00fcsseldorf, D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp A.","family":"Lang","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine II, University of D\u00fcsseldorf, D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adomati","family":"Tom","sequence":"additional","affiliation":[{"name":"Institute of Immunology, University Hospital Essen, Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl S.","family":"Lang","sequence":"additional","affiliation":[{"name":"Institute of Immunology, University Hospital Essen, Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J. 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