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and \u03b3\u03b4 T cells are disparate T cell lineages that can respond to distinct antigens (Ags) via the use of the \u03b1\u03b2 and \u03b3\u03b4 T cell Ag receptors (TCRs), respectively. Here we characterize a population of human T cells, which we term \u03b4/\u03b1\u03b2 T cells, expressing TCRs comprised of a TCR-\u03b4 variable gene (V\u03b41) fused to joining \u03b1 and constant \u03b1 domains, paired with an array of TCR-\u03b2 chains. We demonstrate that these cells, which represent \u223c50% of all V\u03b41(+) human T cells, can recognize peptide- and lipid-based Ags presented by human leukocyte antigen (HLA) and CD1d, respectively. Similar to type I natural killer T (NKT) cells, CD1d-lipid Ag-reactive \u03b4/\u03b1\u03b2 T cells recognized \u03b1-galactosylceramide (\u03b1-GalCer); however, their fine specificity for other lipid Ags presented by CD1d, such as \u03b1-glucosylceramide, was distinct from type I NKT cells. Thus, \u03b4/\u03b1\u03b2TCRs contribute new patterns of Ag specificity to the human immune system. Furthermore, we provide the molecular bases of how \u03b4/\u03b1\u03b2TCRs bind to their targets, with the V\u03b41-encoded region providing a major contribution to \u03b4/\u03b1\u03b2TCR binding. Our findings highlight how components from \u03b1\u03b2 and \u03b3\u03b4TCR gene loci can recombine to confer Ag specificity, thus expanding our understanding of T cell biology and TCR diversity.","bibjson":{"author":[{"initials":"DG","lastname":"Pellicci","name":"Pellicci DG"},{"initials":"AP","lastname":"Uldrich","name":"Uldrich AP"},{"initials":"J","lastname":"Le Nours","name":"Le Nours J"},{"initials":"F","lastname":"Ross","name":"Ross F"},{"initials":"E","lastname":"Chabrol","name":"Chabrol E"},{"initials":"SB","lastname":"Eckle","name":"Eckle SB"},{"initials":"R","lastname":"de Boer","name":"de Boer R"},{"initials":"RT","lastname":"Lim","name":"Lim RT"},{"initials":"K","lastname":"McPherson","name":"McPherson K"},{"initials":"G","lastname":"Besra","name":"Besra G"},{"initials":"AR","lastname":"Howell","name":"Howell AR"},{"initials":"L","lastname":"Moretta","name":"Moretta L"},{"initials":"J","lastname":"McCluskey","name":"McCluskey J"},{"initials":"MH","lastname":"Heemskerk","name":"Heemskerk MH"},{"initials":"S","lastname":"Gras","name":"Gras S"},{"initials":"J","lastname":"Rossjohn","name":"Rossjohn J"},{"initials":"DI","lastname":"Godfrey","name":"Godfrey DI"}],"identifier":[{"id":"10.1084/jem.20141764","type":"doi"},{"id":"25452463","type":"pubmed"}],"issue":[null],"journal":{"iso_abbreviation":"J. Exp. Med.","name":""},"pages":[null],"title":"The molecular bases of \ufffd\ufffd/\ufffd\ufffd\ufffd\ufffd T cell-mediated antigen recognition.","type":"article","url":"https://rupress.org/jem/article/211/13/2599/54601/The-molecular-bases-of-%CE%B4%CE%B1%CE%B2-T-cellmediated-antigen","volume":[null],"year":[2014]},"in_pmc":"N","in_pmce":"Y","open_access":"Y"},"resolution":"3.00","same_as":{"pdbe":{"url":"https://www.ebi.ac.uk/pdbe/entry/pdb/4qrr"},"rcsb":{"url":"https://www.rcsb.org/structure/4qrr"},"stcrdab":{"url":"http://opig.stats.ox.ac.uk/webapps/stcrdab/StrViewer?pdb=4qrr"}},"species":{"common_name":"Human","match_type":"histo:assign_species","scientific_name":"Homo sapiens","slug":"homo_sapiens"},"tcr":{"alpha":{"chains":["D"],"subgroup":null},"beta":{"chains":["E"],"subgroup":"TRBV5"},"mhc_type":"class_i","pdb_code":"4qrr"},"title":"HLA-B*35:01 presenting \"IPSINVHHY\" to Alpha/Beta T cell receptor at 3.00Å resolution","unique_chain_count":5}}