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However, in vitro frequencies of metal\u2010specific T cells and the mechanisms of antigen recognition remain unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here, we utilized a CD154 upregulation assay to quantify Ni<jats:sup>2+<\/jats:sup>\u2010, Co<jats:sup>2+<\/jats:sup>\u2010, and Pd<jats:sup>2+<\/jats:sup>\u2010specific CD4+ T cells in peripheral blood mononuclear cells (PBMC). Involved \u03b1\u03b2 T cell receptor (TCR) repertoires were analyzed by high\u2010throughput sequencing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Peripheral blood mononuclear cells incubation with NiSO<jats:sub>4<\/jats:sub>, CoCl<jats:sub>2<\/jats:sub>, and PdCl<jats:sub>2<\/jats:sub> increased frequencies of CD154\u2009+\u2009CD4+ memory T cells that peaked at ~400\u2009\u03bcM. Activation was TCR\u2010mediated as shown by the metal\u2010specific restimulation of T cell clones. Most abundant were Pd<jats:sup>2+<\/jats:sup>\u2010specific T cells (mean 3.5%, <jats:italic>n<\/jats:italic>\u00a0=\u00a019), followed by Co<jats:sup>2+<\/jats:sup>\u2010 and Ni<jats:sup>2+<\/jats:sup>\u2010specific cells (0.6%, <jats:italic>n<\/jats:italic>\u00a0=\u00a018 and 0.3%, <jats:italic>n<\/jats:italic>\u00a0=\u00a020) in both allergic and non\u2010allergic individuals. A strong overrepresentation of the gene segment TRAV9\u20102 was unique for Ni<jats:sup>2+<\/jats:sup>\u2010specific TCR (28% of TCR) while Co<jats:sup>2+<\/jats:sup> and Pd<jats:sup>2+<\/jats:sup>\u2010specific TCR favorably expressed TRAV2 (8%) and the TRBV4 gene segment family (21%), respectively. As a second, independent mechanism of metal ion recognition, all analyzed metal\u2010specific TCR showed a common overrepresentation of a histidine in the complementarity determining region 3 (CDR3; 15% of \u03b1\u2010chains, 34% of \u03b2\u2010chains). The positions of the CDR3 histidine among metal\u2010specific TCR mirrored those in random repertoires and were conserved among cross\u2010reactive clonotypes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Induced CD154 expression allows a fast and comprehensive detection of Ni<jats:sup>2+<\/jats:sup>\u2010, Co<jats:sup>2+<\/jats:sup>\u2010, and Pd<jats:sup>2+<\/jats:sup>\u2010specific CD4+ T cells. Distinct TCR repertoire features underlie the frequent activation and cross\u2010reactivity of human metal\u2010specific T cells.<\/jats:p><\/jats:sec>","DOI":"10.1111\/all.15494","type":"journal-article","created":{"date-parts":[[2022,8,25]],"date-time":"2022-08-25T12:00:01Z","timestamp":1661428801000},"page":"270-282","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Unique and common <scp>TCR<\/scp> repertoire features of Ni<sup>2+<\/sup>\u2010, Co<sup>2+<\/sup>\u2010, and Pd<sup>2+<\/sup>\u2010specific human <scp>CD154<\/scp>\u00a0+\u2009<scp>CD4<\/scp>+ T cells"],"prefix":"10.1111","volume":"78","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2395-5454","authenticated-orcid":false,"given":"Franziska","family":"Riedel","sequence":"first","affiliation":[{"name":"Dermatotoxicology Study Centre German Federal Institute for Risk Assessment  Berlin Germany"},{"name":"Department of Chemical and Product Safety 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