{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T17:45:46Z","timestamp":1791135946081,"version":"4.1.0"},"reference-count":34,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2004,7,29]],"date-time":"2004-07-29T00:00:00Z","timestamp":1091059200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Eur J Immunol"],"published-print":{"date-parts":[[2004,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The Epstein\u2010Barr virus (EBV) nuclear antigen\u20041 (EBNA1) is the only viral protein regularly expressed in EBV\u2010associated malignancies. Immune recognition of EBNA1 by CD8<jats:sup>+<\/jats:sup> T\u2004cells is prevented by an internal glycine\u2010alanine repeat (GAr) which blocks proteasomal degradation. To test whether EBV\u2010infected cells could be recognized by T\u2004helper cells, human CD4<jats:sup>+<\/jats:sup> T\u2004cell clones specific for EBNA1 were isolated from latently EBV\u2010infected individuals. These T\u2004cells, however, failed to recognize EBV\u2010positive target cells. To investigate whether endogenous presentation of EBNA1 epitopes on MHC class\u2004II was prevented by the GAr domain, a mutant EBV strain with an EBNA1 lacking the GAr (EBNA1\u0394GA) was generated and used to establish an Epstein\u2010Barr virus\u2010immortalized lymphoblastoid B\u2004cell line (LCL). The EBNA1\u0394GA LCL were not recognized by the EBNA1\u2010specific T\u2004cell clones either, indicating that the GAr domain does not mediate this effect. Immune recognition could be restored by overexpression of EBNA1, for which at least 60\u2010fold higher levels of both EBNA1 or EBNA1\u0394GAr protein were required. These results demonstrate that EBNA1 evades direct recognition by CD4<jats:sup>+<\/jats:sup> T\u2004helper cells, since its steady state level is below the threshold required for efficient presentation on MHC class\u2004II. These findings have important implications for the design of immunotherapeutic approaches to target EBV\u2010positive malignancies.<\/jats:p>","DOI":"10.1002\/eji.200324794","type":"journal-article","created":{"date-parts":[[2004,7,29]],"date-time":"2004-07-29T21:05:11Z","timestamp":1091135111000},"page":"2500-2509","source":"Crossref","is-referenced-by-count":51,"title":["Epstein\u2010Barr virus nuclear antigen\u20041 evades direct immune recognition by CD4<sup>+<\/sup> T\u2004helper cells"],"prefix":"10.1002","volume":"34","author":[{"given":"Josef","family":"Mautner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dagmar","family":"Pich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Falk","family":"Nimmerjahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Slavoljub","family":"Milosevic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinesh","family":"Adhikary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heike","family":"Christoph","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Witter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg\u2004W.","family":"Bornkamm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang","family":"Hammerschmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uta","family":"Behrends","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2004,8,5]]},"reference":[{"key":"e_1_2_7_1_2","doi-asserted-by":"publisher","DOI":"10.1006\/smvy.1996.0039"},{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199509143331110"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.2000.0781"},{"key":"e_1_2_7_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-230X(02)84006-4"},{"key":"e_1_2_7_5_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.15.1.405"},{"key":"e_1_2_7_6_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.micro.54.1.19"},{"key":"e_1_2_7_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1832776100"},{"key":"e_1_2_7_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/375685a0"},{"key":"e_1_2_7_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.23.12616"},{"key":"e_1_2_7_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80397-0"},{"key":"e_1_2_7_11_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.165.12.7078"},{"key":"e_1_2_7_12_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.188.12.2199"},{"key":"e_1_2_7_13_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.188.12.2357"},{"key":"e_1_2_7_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/383787a0"},{"key":"e_1_2_7_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.75.8.3740-3752.2001"},{"key":"e_1_2_7_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(95)91150-2"},{"key":"e_1_2_7_17_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.1997.tb00984.x"},{"key":"e_1_2_7_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/9.10.1537"},{"key":"e_1_2_7_19_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.191.10.1649"},{"key":"e_1_2_7_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.75.18.8649-8659.2001"},{"key":"e_1_2_7_21_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.169.3.1593"},{"key":"e_1_2_7_22_2","first-page":"7195","article-title":"Identification of HLA\u2010DP3\u2010restricted peptides from EBNA1 recognized by CD4(+) T\u2004cells.","volume":"62","author":"Voo K. S.","year":"2002","journal-title":"Cancer Res."},{"key":"e_1_2_7_23_2","doi-asserted-by":"publisher","DOI":"10.1097\/00002371-200305000-00005"},{"key":"e_1_2_7_24_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.14.8245"},{"key":"e_1_2_7_25_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.16.7217"},{"key":"e_1_2_7_26_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/16.20.6131"},{"key":"e_1_2_7_27_2","doi-asserted-by":"crossref","first-page":"2407","DOI":"10.1128\/jvi.64.5.2407-2410.1990","article-title":"The average number of molecules of Epstein\u2010Barr nuclear antigen\u20041 per cell does not correlate with the average number of Epstein\u2010Barr virus (EBV) DNA molecules per cell among different clones of EBV\u2010immortalized cells.","volume":"64","author":"Sternas L.","year":"1990","journal-title":"J. Virol."},{"key":"e_1_2_7_28_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.1999.tb01328.x"},{"key":"e_1_2_7_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200323730"},{"key":"e_1_2_7_30_2","first-page":"23","article-title":"Genetic analysis and gene expression with mini\u2010Epstein\u2010Barr virus plasmids.","volume":"174","author":"Kilger E.","year":"2001","journal-title":"Methods Mol. Biol."},{"key":"e_1_2_7_31_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.2660262"},{"key":"e_1_2_7_32_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.9.5188"},{"key":"e_1_2_7_33_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.232381299"},{"key":"e_1_2_7_34_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200324342"}],"container-title":["European Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Feji.200324794","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/eji.200324794","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,10]],"date-time":"2023-10-10T15:04:26Z","timestamp":1696950266000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/eji.200324794"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,8,5]]},"references-count":34,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2004,9]]}},"alternative-id":["10.1002\/eji.200324794"],"URL":"https:\/\/doi.org\/10.1002\/eji.200324794","archive":["Portico"],"relation":{},"ISSN":["0014-2980","1521-4141"],"issn-type":[{"value":"0014-2980","type":"print"},{"value":"1521-4141","type":"electronic"}],"subject":[],"published":{"date-parts":[[2004,8,5]]}}}