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We find that, while not approaching virus-specific CD8+ T cell expansions in magnitude, activated CD4+ T cells specific for epitopes in the latent antigen EBNA2 and four lytic cycle antigens are detected at high frequencies in acute IM blood. They then fall rapidly to values typical of life-long virus carriage where most tetramer-positive cells display conventional memory markers but some, unexpectedly, revert to a naive-like phenotype. In contrast CD4+ T cell responses to EBNA1 epitopes are greatly delayed in IM patients, in line with the well-known but hitherto unexplained delay in EBNA1 IgG antibody responses. We present evidence from an in vitro system that may explain these unusual kinetics. Unlike other EBNAs and lytic cycle proteins, EBNA1 is not naturally released from EBV-infected cells as a source of antigen for CD4+ T cell priming.<\/jats:p>","DOI":"10.1084\/jem.20121437","type":"journal-article","created":{"date-parts":[[2013,4,8]],"date-time":"2013-04-08T21:50:21Z","timestamp":1365457821000},"page":"933-949","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":107,"title":["MHC II tetramers visualize human CD4+ T cell responses to Epstein\u2013Barr virus infection and demonstrate atypical kinetics of the nuclear antigen EBNA1 response"],"prefix":"10.1084","volume":"210","author":[{"given":"Heather M.","family":"Long","sequence":"first","affiliation":[{"name":"School of Cancer Sciences and MRC Centre for Immune Regulation, College of Medicine, University of Birmingham, B15 2TT Birmingham, England, UK 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Odette L.","family":"Chagoury","sequence":"additional","affiliation":[{"name":"School of Cancer Sciences and MRC Centre for Immune Regulation, College of Medicine, University of Birmingham, B15 2TT Birmingham, England, UK 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison M.","family":"Leese","sequence":"additional","affiliation":[{"name":"School of Cancer Sciences and MRC Centre for Immune Regulation, College of Medicine, University of Birmingham, B15 2TT Birmingham, England, UK 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordon B.","family":"Ryan","sequence":"additional","affiliation":[{"name":"School of Cancer Sciences and MRC Centre for Immune Regulation, College of Medicine, University of Birmingham, B15 2TT Birmingham, England, UK 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eddie","family":"James","sequence":"additional","affiliation":[{"name":"Benaroya Research Institute at Virginia Mason, Seattle, WA 98101 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura T.","family":"Morton","sequence":"additional","affiliation":[{"name":"School of Cancer Sciences and MRC Centre for Immune Regulation, College of Medicine, University of Birmingham, B15 2TT Birmingham, England, UK 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel J.M.","family":"Abbott","sequence":"additional","affiliation":[{"name":"School of Cancer Sciences and MRC Centre for Immune Regulation, College of Medicine, University of Birmingham, B15 2TT Birmingham, England, UK 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shereen","family":"Sabbah","sequence":"additional","affiliation":[{"name":"School of Cancer Sciences and MRC Centre for Immune Regulation, College of Medicine, University of Birmingham, B15 2TT Birmingham, England, UK 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Kwok","sequence":"additional","affiliation":[{"name":"Benaroya Research Institute at Virginia Mason, Seattle, WA 98101 2"},{"name":"Department of Medicine, University of Washington, Seattle WA 98195 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan B.","family":"Rickinson","sequence":"additional","affiliation":[{"name":"School of Cancer Sciences and MRC Centre for Immune Regulation, College of Medicine, University of Birmingham, B15 2TT Birmingham, England, UK 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2013,4,8]]},"reference":[{"key":"2023072601534572300_bib1","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1084\/jem.20051287","article-title":"Control of Epstein-Barr virus infection in vitro by T helper cells specific for virion glycoproteins","volume":"203","author":"Adhikary","year":"2006","journal-title":"J. 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