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The development of long\u2010lasting effective FMD vaccines would greatly benefit the global FMD control programme. Deep analysis of adaptive immunity in cattle vaccinated against FMD is technically challenging due to the lack of species\u2010specific tools. In this study, we aimed to identify CD4<jats:sup>+<\/jats:sup> T\u2010cell epitopes in the FMD virus (FMDV) capsid and to phenotype the CD4<jats:sup>+<\/jats:sup> T cells that recognize them using bovine major histocompatibility complex (BoLA) class II tetramer. A BoLA class II tetramer based on the <jats:italic>DRA<\/jats:italic>\/<jats:italic>DRB3*020<\/jats:italic>:<jats:italic>02<\/jats:italic> allele and FMDV antigen\u2010stimulated PBMCs from bovine vaccinates were used to successfully identify four epitopes in the FMDV capsid, three of which have not been previously reported; two epitopes were identified in the structural protein VP1, one in VP3 and one in VP4. Specificity of the three novel epitopes was confirmed by proliferation assay. All epitope\u2010expanded T\u2010cell populations produced IFN\u2010\u03b3 <jats:italic>in vitro<\/jats:italic>, indicating a long\u2010lasting Th1 cell phenotype after FMD vaccination. VP3\u2010specific CD4<jats:sup>+<\/jats:sup> T cells exhibited the highest frequency amongst the identified epitopes, comprising &gt;0\u00b7004% of the CD4<jats:sup>+<\/jats:sup> T\u2010cell population. CD45RO<jats:sup>+<\/jats:sup>CCR7<jats:sup>+<\/jats:sup> defined central memory CD4<jats:sup>+<\/jats:sup> T\u2010cell subpopulations were present in higher frequency in FMDV\u2010specific CD4<jats:sup>+<\/jats:sup> T\u2010cell populations from FMD\u2010vaccinated cattle <jats:italic>ex vivo<\/jats:italic>. This indicates an important role in maintaining cell adaptive immunity after FMD vaccination. Notably, FMDV epitope\u2010loaded tetramers detected the presence of FMDV\u2010specific CD4<jats:sup>+<\/jats:sup> T cells in bovine PBMC more than four years after vaccination. This work contributes to our understanding of vaccine efficacy.<\/jats:p>","DOI":"10.1111\/imm.13367","type":"journal-article","created":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T13:02:30Z","timestamp":1621342950000},"page":"266-278","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["The detection of long\u2010lasting memory foot\u2010and\u2010mouth disease (FMD) virus serotype O\u2010specific CD4<sup>+<\/sup> T cells from FMD\u2010vaccinated cattle by bovine major histocompatibility complex class II tetramer"],"prefix":"10.1111","volume":"164","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4271-0150","authenticated-orcid":false,"given":"Shuya","family":"Mitoma","sequence":"first","affiliation":[{"name":"Department of Veterinary Medicine Faculty of Agriculture University of Miyazaki Miyazaki Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigid 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