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Here, we identify the progeny of this unconventional lineage in antigen-inexperienced blood. These unconventional T cells (UTCs) in thymus and blood share a transcriptomic profile, characterized by hallmark transcription factors (i.e., ZNF683 and IKZF2), and a polyclonal TCR repertoire with autoreactive features, exhibiting a bias toward early TCR\u03b1 chain rearrangements. Single-cell RNA sequencing confirms a common developmental trajectory between the thymic and blood UTCs and clearly delineates this unconventional lineage in blood. Besides MME+ recent thymic emigrants, effector-like clusters are identified in this heterogeneous lineage. Expression of Helios and KIR and a decreased CD8\u03b2 expression are characteristics of this lineage. This UTC lineage could be identified in adult blood and intestinal tissues. In summary, our data provide a comprehensive characterization of the polyclonal unconventional lineage in antigen-inexperienced blood and identify the adult progeny.<\/jats:p>","DOI":"10.1084\/jem.20220942","type":"journal-article","created":{"date-parts":[[2023,2,28]],"date-time":"2023-02-28T02:21:00Z","timestamp":1677550860000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":24,"title":["Single-cell profiling identifies a novel human polyclonal unconventional T cell lineage"],"prefix":"10.1084","volume":"220","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9372-1920","authenticated-orcid":true,"given":"Lore","family":"Billiet","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00cv9y106","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Diagnostic Sciences, Ghent University 1 , Ghent, 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