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CD4<jats:sup>+<\/jats:sup>T cells provide an auxiliary function(s) for CD8<jats:sup>+<\/jats:sup>T-cell survival; however, their direct contribution to control of virus replication and pathology is unclear. To examine a direct role of CD4<jats:sup>+<\/jats:sup>T cells in viral clearance and pathology, pathogenesis was compared in mice deficient in both perforin and IFN-\u03b3 that were selectively reconstituted for these functions via transfer of virus-specific memory CD4<jats:sup>+<\/jats:sup>T cells. CD4<jats:sup>+<\/jats:sup>T cells from immunized wild-type, perforin-deficient, and IFN-\u03b3-deficient donors all initially reduced virus replication. However, prolonged viral control by IFN-\u03b3-competent donors suggested that IFN-\u03b3 is important for sustained virus control. Local release of IFN-\u03b3 was evident by up-regulation of class II molecules on microglia in recipients of IFN-\u03b3 producing CD4<jats:sup>+<\/jats:sup>T cells. CD4<jats:sup>+<\/jats:sup>T-cell-mediated antiviral activity correlated with diminished clinical symptoms, pathology, and demyelination. Both wild-type donor CD90.1 and recipient CD90.2 CD4<jats:sup>+<\/jats:sup>T cells trafficked into the central nervous system (CNS) parenchyma and localized to infected white matter, correlating with decreased numbers of virus-infected oligodendrocytes in the CNS. These data support a direct, if limited, antiviral role for CD4<jats:sup>+<\/jats:sup>T cells early during acute JHMV encephalomyelitis. Although the antiviral effector mechanism is initially independent of IFN-\u03b3 secretion, sustained control of CNS virus replication by CD4<jats:sup>+<\/jats:sup>T cells requires IFN-\u03b3.<\/jats:p>","DOI":"10.1128\/jvi.01762-07","type":"journal-article","created":{"date-parts":[[2007,12,20]],"date-time":"2007-12-20T01:53:51Z","timestamp":1198115631000},"page":"2130-2139","update-policy":"http:\/\/dx.doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":40,"title":["CD4 T Cells Contribute to Virus Control and Pathology following Central Nervous System Infection with Neurotropic Mouse Hepatitis Virus"],"prefix":"10.1128","volume":"82","author":[{"given":"Stephen A.","family":"Stohlman","sequence":"first","affiliation":[{"name":"Departments of Neurology"},{"name":"Pathology"},{"name":"Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, California 90033"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David R.","family":"Hinton","sequence":"additional","affiliation":[{"name":"Pathology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beatriz","family":"Parra","sequence":"additional","affiliation":[{"name":"Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, California 90033"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roscoe","family":"Atkinson","sequence":"additional","affiliation":[{"name":"Pathology"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cornelia C.","family":"Bergmann","sequence":"additional","affiliation":[{"name":"Departments of Neurology"},{"name":"Pathology"},{"name":"Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, California 90033"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"crossref","first-page":"3379","DOI":"10.4049\/jimmunol.163.6.3379","volume":"163","year":"1999","unstructured":"Bergmann, C., J. 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