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TCR repertoires for \u03b1\/\u03b2\/\u03b4\/\u03b3 chains, TCR diversity, and V\/J usage were determined by next\u2010generation sequencing. TCR \u03b2 chain repertoires were compared with affectation status using a novel clustering method, Grouping of Lymphocyte Interactions by Paratope Hotspots (GLIPH). Cytomegalovirus (CMV)\u2010IgG was measured in an additional 113 MS patients and 93 HCs. Regulatory T cells (Tregs) were measured by flow cytometry.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>TCR diversity for all four chains decreased with age. TCR\u03b1 and TCR\u03b2 diversity was higher in MS patients (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.0015 and 0.024, respectively), even after age correction. <jats:italic>TRAJ56<\/jats:italic> and <jats:italic>TRBV4\u20103<\/jats:italic> were more prevalent in MS patients than in HCs (<jats:italic>p<jats:sup>corr<\/jats:sup><\/jats:italic>\u00a0=\u00a00.027 and 0.040, respectively). GLIPH consolidated 208,674 TCR clones from MS patients into 1,294 clusters, among which two candidate clusters were identified. The <jats:italic>TRBV4\u20103<\/jats:italic> cluster was shared by <jats:italic>HLA\u2010DRB1*04:05<\/jats:italic>\u2010positive patients (87.5%) and predicted to recognize CMV peptides (CMV\u2010TCR). MS Severity Score (MSSS) was lower in patients with CMV\u2010TCR than in those without (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.037). CMV\u2010IgG\u2010positivity was associated with lower MSSS in <jats:italic>HLA\u2010DRB1*04:05<\/jats:italic> carriers (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.0053). <jats:italic>HLA\u2010DRB1*04:05<\/jats:italic>\u2010positive individuals demonstrated higher CMV\u2010IgG titers than <jats:italic>HLA\u2010DRB1*04:05<\/jats:italic>\u2010negative individuals (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.017). CMV\u2010IgG\u2010positive patients had more Tregs than CMV\u2010IgG\u2010negative patients (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.054).<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>High TCR\u03b1\/TCR\u03b2 diversity, regardless of age, is characteristic of MS. Association of a CMV\u2010recognizing TCR with mild disability indicates CMV\u2019s protective role in <jats:italic>HLA\u2010DRB1*04:05<\/jats:italic>\u2010positive MS.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51264","type":"journal-article","created":{"date-parts":[[2021,1,6]],"date-time":"2021-01-06T16:41:06Z","timestamp":1609951266000},"page":"163-176","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["A new clustering method identifies multiple sclerosis\u2010specific T\u2010cell receptors"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7754-3770","authenticated-orcid":false,"given":"Fumie","family":"Hayashi","sequence":"first","affiliation":[{"name":"Department of Neurology Graduate School of Medical Sciences Kyushu University Fukuoka 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