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Adv."],"published-print":{"date-parts":[[2026,2,13]]},"abstract":"<jats:p>T cell repertoires of different individuals occasionally converge on the same T cell receptor (TCR) sequence as a solution to target immunodominant epitopes. A complete mapping of these \u201cpublic\u201d TCR specificities may enable a global understanding of population-level immune histories. Here, we sought to determine the antigen specificities of public TCRs with unknown target identity. We developed a functional screening workflow in which we screen panels of TCRs for reactivity to individual viral genomes or to ~1000 viral reference strains and then sort out the immunogenic peptides by labeling antigen-presenting cells that are in proximity to activated T cells. Using this workflow, we identified the target specificities of T cells that are circulating in up to 14% of individuals, including a pre\u2013COVID-19 seasonal coronavirus-reactive TCR that cross-reacts with peptides within pandemic coronaviruses; an influenza B\u2013reactive TCR that targets a highly conserved epitope; and TCRs targeting Herpesviridae family viruses that cause long-term latent infections. Our results demonstrate an efficient strategy to reveal public T cell memories de novo, offering a window into shared immune exposures.<\/jats:p>","DOI":"10.1126\/sciadv.aeb1732","type":"journal-article","created":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T18:59:07Z","timestamp":1771009147000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["De novo identification of the specificities of recurrently identified human T cell receptors"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7010-1603","authenticated-orcid":true,"given":"Mithila","family":"Kasbe","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, Yale School of Medicine, 330 Cedar St., New Haven, CT 06519, USA."},{"name":"Human and Translational Immunology Program, Yale School of Medicine, 300 Cedar St., New Haven, CT 06519, USA."},{"name":"Cancer Immunology Program, Yale Cancer Center, 35 Park St., New Haven, CT 06519, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3480-6152","authenticated-orcid":true,"given":"Berkay","family":"Yahsi","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Yale School of Medicine, 330 Cedar St., New Haven, CT 06519, USA."},{"name":"Human and Translational Immunology Program, Yale School of Medicine, 300 Cedar St., New Haven, CT 06519, USA."},{"name":"Cancer Immunology Program, Yale Cancer Center, 35 Park St., New Haven, CT 06519, USA."},{"name":"Department of Pathology, Yale School of Medicine, 310 Cedar St., New Haven, CT 06519, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5927-2014","authenticated-orcid":true,"given":"Kalyn","family":"Whitehead","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Yale School of Medicine, 330 Cedar St., New Haven, CT 06519, USA."},{"name":"Human and Translational Immunology Program, Yale School of Medicine, 300 Cedar St., New Haven, CT 06519, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7068-4570","authenticated-orcid":true,"given":"Jiwon","family":"Oh","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Yale School of Medicine, 330 Cedar St., New Haven, CT 06519, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mashwiyat","family":"Mosharraf","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Yale School of Medicine, 330 Cedar St., New Haven, CT 06519, USA."},{"name":"Human and Translational Immunology Program, Yale School of Medicine, 300 Cedar St., New Haven, CT 06519, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kayla","family":"Sohn","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Yale School of Medicine, 330 Cedar St., New Haven, CT 06519, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Trinh","family":"Phan","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Yale School of Medicine, 330 Cedar St., New Haven, CT 06519, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9576-9589","authenticated-orcid":true,"given":"Mark N.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Yale School of Medicine, 330 Cedar St., New Haven, CT 06519, USA."},{"name":"Human and Translational Immunology Program, Yale School of Medicine, 300 Cedar St., New Haven, CT 06519, USA."},{"name":"Cancer Immunology Program, Yale Cancer Center, 35 Park St., New Haven, CT 06519, USA."},{"name":"Department of Pathology, Yale School of Medicine, 310 Cedar St., New Haven, CT 06519, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3822"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.150070"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.38358"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.151849"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz874"},{"key":"e_1_3_2_7_2","doi-asserted-by":"crossref","unstructured":"M. Messemaker B. P. Y. Kwee \u017d. Moravec D. \u00c1lvarez-Salmoral J. Urbanus S. de Paauw J. Geerligs R. Voogd B. Morris A. Guislain M. Mu\u00dfmann Y. Winkler M. Steinmetz M. Iras E. Marcus J. Teuwen A. Perrakis R. L. Beijersbergen W. Scheper T. N. Schumacher A functionally validated TCR-pMHC database for TCR specificity model development. bioRxiv 651095 [Preprint] (2025). https:\/\/doi.org\/10.1101\/2025.04.28.651095.","DOI":"10.1101\/2025.04.28.651095"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/CVI.00278-10"},{"key":"e_1_3_2_9_2","first-page":"1","article-title":"Prevalence of herpes simplex virus type 1 and type 2 in persons aged 14-49: United States, 2015-2016","author":"McQuillan G.","year":"2018","unstructured":"G. McQuillan, D. Kruszon-Moran, E. W. Flagg, R. Paulose-Ram, Prevalence of herpes simplex virus type 1 and type 2 in persons aged 14-49: United States, 2015-2016. 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E. Blum R. Kong E. A. Schulman F. M. Chen R. Upadhyay G. Romero-Meza D. R. Littman M. A. Fischbach K. Nagashima E. S. Sattely Discovery and characterization of dietary antigens in oral tolerance. bioRxiv 593976 [Preprint] (2024). https:\/\/doi.org\/10.1101\/2024.05.26.593976.","DOI":"10.1101\/2024.05.26.593976"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2103485"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(24)00319-2"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-021-00292-8"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.05.035"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2025.03.018"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-05-023069"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04494-7"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07018-7"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aag3187"},{"key":"e_1_3_2_65_2","unstructured":"W. Ferlin N. Fischer G. Elson O. Leger Anti-interferon gamma antibodies and methods of use thereof US Patent 9682142 (2017)."}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.aeb1732","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T19:00:45Z","timestamp":1771009245000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.aeb1732"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,13]]},"references-count":64,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026,2,13]]}},"alternative-id":["10.1126\/sciadv.aeb1732"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.aeb1732","relation":{},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,13]]},"assertion":[{"value":"2025-08-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-13","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eaeb1732"}}