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Using HLA class II tetramers, we studied the functional properties and clonotypic architecture of EBV-specific CD4+ T cells in patients with infectious mononucleosis, a symptomatic manifestation of primary EBV infection, and in long-term healthy carriers of EBV. We found that primary infection elicited oligoclonal expansions of TH1-like EBV-specific CD4+ T cells armed with cytotoxic proteins that responded immediately ex vivo to challenge with EBV-infected B cells. Importantly, these acutely generated cytotoxic CD4+ T cells were highly activated and transcriptionally distinct from classically described cytotoxic CD4+ memory T cells that accumulate during other persistent viral infections, including CMV and HIV. In contrast, EBV-specific memory CD4+ T cells displayed increased cytokine polyfunctionality but lacked cytotoxic activity. These findings suggested an important effector role for acutely generated cytotoxic CD4+ T cells that could potentially be harnessed to improve the efficacy of vaccines against EBV.<\/jats:p>","DOI":"10.4049\/jimmunol.1900377","type":"journal-article","created":{"date-parts":[[2019,7,15]],"date-time":"2019-07-15T20:45:13Z","timestamp":1563223513000},"page":"1276-1287","source":"Crossref","is-referenced-by-count":51,"title":["Primary EBV Infection Induces an Acute Wave of Activated Antigen-Specific Cytotoxic CD4+ T Cells"],"prefix":"10.1093","volume":"203","author":[{"given":"Benjamin J","family":"Meckiff","sequence":"first","affiliation":[{"name":"Institute of Immunology and Immunotherapy, University of Birmingham , Edgbaston, Birmingham B15 2TT ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9856-2938","authenticated-orcid":false,"given":"Kristin","family":"Ladell","sequence":"additional","affiliation":[{"name":"Division of Infection and Immunity, Cardiff University School of Medicine , Cardiff CF14 4XN ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7021-5934","authenticated-orcid":false,"given":"James E","family":"McLaren","sequence":"additional","affiliation":[{"name":"Division of Infection and Immunity, Cardiff University School of Medicine , Cardiff CF14 4XN ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordon B","family":"Ryan","sequence":"additional","affiliation":[{"name":"Institute of Immunology and Immunotherapy, University of Birmingham , Edgbaston, Birmingham B15 2TT ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison M","family":"Leese","sequence":"additional","affiliation":[{"name":"Institute of Immunology and Immunotherapy, University of Birmingham , Edgbaston, Birmingham B15 2TT ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7217-5729","authenticated-orcid":false,"given":"Eddie A","family":"James","sequence":"additional","affiliation":[{"name":"Tetramer Core Laboratory, Diabetes Program, Benaroya Research Institute at Virginia Mason , Seattle, WA 98101"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9416-2737","authenticated-orcid":false,"given":"David A","family":"Price","sequence":"additional","affiliation":[{"name":"Division of Infection and Immunity, Cardiff University School of Medicine , Cardiff CF14 4XN ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2139-8292","authenticated-orcid":false,"given":"Heather M","family":"Long","sequence":"additional","affiliation":[{"name":"Institute of Immunology and Immunotherapy, University of Birmingham , Edgbaston, Birmingham B15 2TT ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,9,1]]},"reference":[{"key":"2025030417541669800_r1","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1038\/nri3152","article-title":"Expanding roles for CD4+ T cells in immunity to viruses","volume":"12","author":"Swain","year":"2012","journal-title":"Nat. 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