{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T20:15:30Z","timestamp":1791404130778,"version":"4.3.3"},"reference-count":83,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"6815","funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AI136514"],"award-info":[{"award-number":["AI136514"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AI144616"],"award-info":[{"award-number":["AI144616"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AI165077"],"award-info":[{"award-number":["AI165077"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R35GM141457"],"award-info":[{"award-number":["R35GM141457"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AI187063"],"award-info":[{"award-number":["AI187063"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-19-CE45-0018"],"award-info":[{"award-number":["ANR-19-CE45-0018"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["\u201cRESPOND\u201d (101185627)"],"award-info":[{"award-number":["\u201cRESPOND\u201d (101185627)"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Foundation pour la Recherch\u00e9 Medical","award":["EQU202503019997"],"award-info":[{"award-number":["EQU202503019997"]}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Science"],"published-print":{"date-parts":[[2026,9,3]]},"abstract":"<jats:p>Combinatorial pairing of independently recombined T cell receptor (TCR) \u03b1- and \u03b2-chains is central to diversifying the TCR repertoire. Although sequence motifs in one chain correlate with epitope recognition, the extent to which a single chain dictates specificity remains unclear. Here, we systematically tested TCR chain coupling constraints by enforcing the pairing of individual chains with hundreds of thousands of partners. Although most chains paired stably, the preservation of epitope specificity was rare and highly variable, with the frequency of compatible partners ranging from ~10 to &lt;0.1%. This approach identified &gt;70,000 epitope-specific TCRs across 10 epitopes. Our work illuminates the distinct contributions of TCR chains, highlights the limitations of single-chain data, and provides an experimental and analytical framework for refining TCR-peptide-major histocompatibility complex specificity inference.<\/jats:p>","DOI":"10.1126\/science.adx3863","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T18:00:43Z","timestamp":1788458443000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":2,"title":["Uneven TCR chain pairing constraints govern epitope recognition"],"prefix":"10.1126","volume":"393","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9884-6351","authenticated-orcid":true,"given":"Anastasia A.","family":"Minervina","sequence":"first","affiliation":[{"name":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0773-1204","authenticated-orcid":true,"given":"Mikhail V.","family":"Pogorelyy","sequence":"additional","affiliation":[{"name":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1652-4023","authenticated-orcid":true,"given":"Koshlan","family":"Mayer-Blackwell","sequence":"additional","affiliation":[{"name":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricky","family":"Tirtakusuma","sequence":"additional","affiliation":[{"name":"Department of Host-Microbe Interactions, St. Jude Children\u2019s Research Hospital, Memphis, TN, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6860-5079","authenticated-orcid":true,"given":"Stefan A.","family":"Schattgen","sequence":"additional","affiliation":[{"name":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7627-2166","authenticated-orcid":true,"given":"Andrew","family":"Fiore-Gartland","sequence":"additional","affiliation":[{"name":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2686-5702","authenticated-orcid":true,"given":"Aleksandra M.","family":"Walczak","sequence":"additional","affiliation":[{"name":"Laboratoire de physique de l\u2019\u00c9cole Normale Sup\u00e9rieure, CNRS, PSL Universit\u00e9, Sorbonne Universit\u00e9, and Universit\u00e9 de Paris Cit\u00e9, Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5456-9361","authenticated-orcid":true,"given":"Thierry","family":"Mora","sequence":"additional","affiliation":[{"name":"Laboratoire de physique de l\u2019\u00c9cole Normale Sup\u00e9rieure, CNRS, PSL Universit\u00e9, Sorbonne Universit\u00e9, and Universit\u00e9 de Paris Cit\u00e9, Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0224-6464","authenticated-orcid":true,"given":"Philip","family":"Bradley","sequence":"additional","affiliation":[{"name":"Computational Biology Program, Fred Hutchinson Cancer Center, Seattle, WA, USA."},{"name":"Institute for Protein Design, University of Washington, Seattle, WA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7955-0256","authenticated-orcid":true,"given":"Paul G.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3504"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0504016102"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri3818"},{"key":"e_1_3_2_5_2","doi-asserted-by":"crossref","unstructured":"T. Mora A. Walczak Quantifying lymphocyte receptor diversity. arXiv:1604.00487 [q-bio.PE] (2016). 10.1101\/046870","DOI":"10.1101\/046870"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-063011-092449"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1207532"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abd2321"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1537-2995.2003.00309.x"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/gzq001"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2024.07.014"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt0792-779"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05371-z"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1101\/2024.05.24.595718"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2408696121"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2213264120"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1488860"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3822"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.ads5589"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2022.09.004"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2024.11.009"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4004"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1401717"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02503"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1007714"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1006874"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature22976"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature22383"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.53704"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-022-01578-0"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-47461-8"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.82813"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20130958"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.189.12.1907"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4866"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri3328"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2024.101469"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-025-02910-0"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuno.2024.100045"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adk3060"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-018-0304-8"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-018-0305-7"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abf4001"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.07.009"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.10.024"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.03.047"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12444-7"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41421-022-00386-2"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0335-z"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-024-02210-6"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-024-02248-6"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1101\/2025.10.24.684243"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-025-02907-9"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abe9124"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2023.04.010"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1102661"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1212755109"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac190"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1111\/imm.12499"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.12.026"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkg070"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1500215"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2960"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3364"},{"key":"e_1_3_2_65_2","unstructured":"A. Minervina M. Pogorelyy P. Thomas Uneven TCR chain pairing constraints govern epitope recognition Zenodo (2025); https:\/\/doi.org\/10.5281\/ZENODO.14885005."},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1004503"},{"key":"e_1_3_2_67_2","unstructured":"52R Core Team R: A language and environment for statistical computing (R Foundation for Statistical Computing 2021); www.R-project.org\/."},{"key":"e_1_3_2_68_2","unstructured":"Posit team RStudio: Integrated Development Environment for R (Posit Software 2025); https:\/\/www.posit.co\/."},{"key":"e_1_3_2_69_2","unstructured":"T. Barrett M. Dowle A. Srinivasan J. Gorecki M. Chirico T. Hocking B. Schwendinger I. Krylov Data.Table: Extension of \u201cdata.Frame\u201d (2025); https:\/\/r-datatable.com."},{"key":"e_1_3_2_70_2","unstructured":"H. Wickham R. Fran\u00e7ois L. Henry K. M\u00fcller D. Vaughan Dplyr: A Grammar of Data Manipulation (2025); https:\/\/dplyr.tidyverse.org."},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.68605"},{"key":"e_1_3_2_72_2","unstructured":"K. Mayer-Blackwell kmayerb\/tcrdistgpu: Manuscript version 1.0 version v1.0-manuscript Zenodo (2026); https:\/\/doi.org\/10.5281\/ZENODO.20944403."},{"key":"e_1_3_2_73_2","doi-asserted-by":"publisher","DOI":"10.32614\/RJ-2014-011"},{"key":"e_1_3_2_74_2","first-page":"1","article-title":"The igraph software package for complex network research. InterJournal","author":"Cs\u00e1rdi G.","year":"2006","unstructured":"G. Cs\u00e1rdi, T. Nepusz, The igraph software package for complex network research. InterJournal. Complex Syst. 1695, 1\u20139 (2006).","journal-title":"Complex Syst."},{"key":"e_1_3_2_75_2","doi-asserted-by":"publisher","DOI":"10.1609\/icwsm.v3i1.13937"},{"key":"e_1_3_2_76_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btz035"},{"key":"e_1_3_2_77_2","unstructured":"P. Bradley E. Ball phbradley\/TCRdock: v2.0.1\u2013zenodo DOI version v2.0.1 Zenodo (2026); https:\/\/doi.org\/10.5281\/ZENODO.20938245."},{"key":"e_1_3_2_78_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03819-2"},{"key":"e_1_3_2_79_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07487-w"},{"key":"e_1_3_2_80_2","doi-asserted-by":"crossref","unstructured":"S. Passaro G. Corso J. Wohlwend M. Reveiz S. Thaler V. R. Somnath N. Getz T. Portnoi J. Roy H. Stark D. Kwabi-Addo D. Beaini T. Jaakkola R. Barzilay Boltz-2: Towards Accurate and Efficient Binding Affinity Prediction. bioRxiv 2025.06.14.659707 [Preprint] (2025); 10.1101\/2025.06.14.659707v1.","DOI":"10.1101\/2025.06.14.659707"},{"key":"e_1_3_2_81_2","doi-asserted-by":"crossref","unstructured":"N. Corley S. Mathis R. Krishna M. S. Bauer T. R. Thompson W. Ahern M. W. Kazman R. I. Brent K. Didi A. Kubaney L. McHugh A. Nagle A. Favor M. Kshirsagar P. Sturmfels Y. Li J. Butcher B. Qiang L. L. Schaaf R. Mitra K. Campbell O. Zhang R. Weissman I. R. Humphreys Q. Cong J. Funk S. Sonthalia P. Li\u00f2 D. Baker F. DiMaio Accelerating Biomolecular Modeling with AtomWorks and RF3. bioRxiv 2025.08.14.670328 [Preprint] (2025); 10.1101\/2025.08.14.670328v1.","DOI":"10.1101\/2025.08.14.670328"},{"key":"e_1_3_2_82_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq007"},{"key":"e_1_3_2_83_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1008394"},{"key":"e_1_3_2_84_2","doi-asserted-by":"crossref","unstructured":"H. Wickham Ggplot2: Elegant Graphics for Data Analysis (Springer 2016); https:\/\/ggplot2.tidyverse.org.","DOI":"10.1007\/978-3-319-24277-4_9"}],"container-title":["Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/science.adx3863","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T18:00:56Z","timestamp":1788458456000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/science.adx3863"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,3]]},"references-count":83,"journal-issue":{"issue":"6815","published-print":{"date-parts":[[2026,9,3]]}},"alternative-id":["10.1126\/science.adx3863"],"URL":"https:\/\/doi.org\/10.1126\/science.adx3863","relation":{},"ISSN":["0036-8075","1095-9203"],"issn-type":[{"value":"0036-8075","type":"print"},{"value":"1095-9203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,3]]},"assertion":[{"value":"2025-03-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-06","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-03","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadx3863"}}