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Here, we studied the roles of these signaling factors in the host response to systemic infection with lymphocytic choriomeningitis virus (LCMV). In wild-type (WT) mice and mice lacking either STAT2 or IRF9, LCMV infection was nonlethal, and the virus either was cleared (WT) or established persistence (STAT2 knockout [KO] and IRF9 KO). However, in the case of STAT1 KO mice, LCMV infection was lethal and accompanied by severe multiorgan immune pathology, elevated expression of various cytokine genes in tissues, and cytokines in the serum. This lethal phenotype was unaltered by the coabsence of the gamma interferon (IFN-\u03b3) receptor and hence was not dependent on IFN-\u03b3. Equally, the disease was not due to a combined defect in type I and type II IFN signaling, as IRF9 KO mice lacking the IFN-\u03b3 receptor survived infection with LCMV. Clearance of LCMV is mediated normally by CD8<jats:sup>+<\/jats:sup>T cells. However, the depletion of these cells in LCMV-infected STAT1 KO mice was delayed, but did not prevent, lethality. In contrast, depletion of CD4<jats:sup>+<\/jats:sup>T cells prevented lethality in LCMV-infected STAT1 KO mice and was associated with a reduction in tissue immune pathology. These studies highlight a fundamental difference in the role of STAT1 versus STAT2 and IRF9. While all three factors are required to limit viral replication and spread, only STAT1 has the unique function of preventing the emergence of a lethal antiviral CD4<jats:sup>+<\/jats:sup>T-cell response.<\/jats:p>","DOI":"10.1128\/jvi.07147-11","type":"journal-article","created":{"date-parts":[[2012,4,12]],"date-time":"2012-04-12T05:16:50Z","timestamp":1334207810000},"page":"6932-6946","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":49,"title":["Mice Deficient in STAT1 but Not STAT2 or IRF9 Develop a Lethal CD4<sup>+<\/sup>T-Cell-Mediated Disease following Infection with Lymphocytic Choriomeningitis Virus"],"prefix":"10.1128","volume":"86","author":[{"given":"Markus J.","family":"Hofer","sequence":"first","affiliation":[{"name":"School of Molecular Bioscience and the Bosch Institute, University of Sydney, Sydney, NSW, Australia"},{"name":"Department of Neuropathology, Philipps University Marburg, Marburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Li","sequence":"additional","affiliation":[{"name":"School of Molecular Bioscience and the Bosch Institute, University of Sydney, Sydney, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Manders","sequence":"additional","affiliation":[{"name":"School of Molecular Bioscience and the Bosch Institute, University of Sydney, Sydney, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael","family":"Terry","sequence":"additional","affiliation":[{"name":"Department of Pathology and the Bosch Institute, University of Sydney, Sydney, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sue Ling","family":"Lim","sequence":"additional","affiliation":[{"name":"School of Molecular Bioscience and the Bosch Institute, University of Sydney, Sydney, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J. 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