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However, the contributions of CD4 T cell help to antiviral CD8 T cell immunity during central nervous system (CNS) infection are not well established. Encephalitis induced by the sublethal coronavirus JHMV was used to identify when CD4 T cells regulate CD8 T cell responses following CNS infection. Peripheral expansion of virus-specific CD8 T cells was impaired when CD4 T cells were ablated prior to infection but not at 4 days postinfection. Delayed CD4 T cell depletion abrogated CD4 T cell recruitment to the CNS but only slightly diminished CD8 T cell recruitment. Nevertheless, the absence of CNS CD4 T cells was associated with reduced gamma interferon (IFN-\u03b3) and granzyme B expression by infiltrating CD8 T cells, increased CD8 T cell apoptosis, and impaired control of infectious virus. CD4 T cell depletion subsequent to CD4 T cell CNS migration restored CD8 T cell activity and virus control. Analysis of \u03b3c-dependent cytokine expression indicated interleukin-21 (IL-21) as a primary candidate optimizing CD8 T cell activity within the CNS. These results demonstrate that CD4 T cells play critical roles in both enhancing peripheral activation of CD8 T cells and prolonging their antiviral function within the CNS. The data highlight the necessity for temporally and spatially distinct CD4 T cell helper functions in sustaining CD8 T cell activity during CNS infection.<\/jats:p>","DOI":"10.1128\/jvi.06797-11","type":"journal-article","created":{"date-parts":[[2011,12,29]],"date-time":"2011-12-29T02:00:03Z","timestamp":1325124003000},"page":"2416-2427","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":92,"title":["CD4 T Cells Promote CD8 T Cell Immunity at the Priming and Effector Site during Viral Encephalitis"],"prefix":"10.1128","volume":"86","author":[{"given":"Timothy W.","family":"Phares","sequence":"first","affiliation":[{"name":"Departments of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen A.","family":"Stohlman","sequence":"additional","affiliation":[{"name":"Departments of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihyun","family":"Hwang","sequence":"additional","affiliation":[{"name":"Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Booki","family":"Min","sequence":"additional","affiliation":[{"name":"Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Hinton","sequence":"additional","affiliation":[{"name":"Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelia C.","family":"Bergmann","sequence":"additional","affiliation":[{"name":"Departments of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0952-7915(00)00103-5"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200939939"},{"key":"e_1_3_2_4_2","doi-asserted-by":"crossref","first-page":"3379","DOI":"10.4049\/jimmunol.163.6.3379","article-title":"Inverted immunodominance and impaired cytolytic function of CD8+ T cells during viral persistence in the central nervous system","volume":"163","author":"Bergmann CC","year":"1999","unstructured":"BergmannCC AltmanJD HintonD StohlmanSA. 1999. 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