{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:28:12Z","timestamp":1785403692276,"version":"3.56.0"},"reference-count":84,"publisher":"National Academy of Sciences","issue":"23","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI17665"],"award-info":[{"award-number":["R01AI17665"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM118166"],"award-info":[{"award-number":["R35GM118166"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007316","name":"HHS | NIH | NCI | Division of Cancer Prevention, National Cancer Institute","doi-asserted-by":"publisher","award":["R37CA259177"],"award-info":[{"award-number":["R37CA259177"]}],"id":[{"id":"10.13039\/100007316","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,6,9]]},"abstract":"<jats:p>\n                    T cell receptor (TCR) restriction by highly polymorphic major histocompatibility complex (MHC) proteins is a foundation of cellular immunity. Although the effects of MHC polymorphisms on peptide binding and selection are well established, how micropolymorphisms within MHC supertypes impact immune recognition is poorly understood. Here, we identified a mechanism through which the micropolymorphisms in two closely related HLA-A3 superfamily members govern TCR specificity. We previously showed that TCRs specific for a public neoantigen arising from a\n                    <jats:italic toggle=\"yes\">PIK3CA<\/jats:italic>\n                    oncogenic hotspot mutation restricted by HLA-A*03:01 were unable to recognize the same epitope in the context of HLA-A*03:02 despite equivalent processing and presentation by both alleles. We found here that the two micropolymorphisms distinguishing A*03:02 from A*03:01 prevent TCR binding not by altering peptide binding or static structures, but by altering the conformational ensemble of the neoantigen, preventing it from adopting a binding-permissive state. The effect is rooted in how the two polymorphic sites interact with other covarying, evolutionarily coupled polymorphisms, reflecting a cross-groove network of interactions that controls the conformational adaptability of the peptide\/HLA complex. We suggest polymorphism-dependent adaptability reflects an evolved feature of class I MHC proteins, further diversifying epitopes and contributing to how TCRs and other immunoreceptors differentiate between antigens. Beyond this mechanistic insight, our findings emphasize the need for high-resolution HLA typing in efforts across immunology, including antigen-specific immunotherapy.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2602949123","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T19:33:41Z","timestamp":1780342421000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["HLA micropolymorphisms confine neoantigen conformational adaptability and guide T cell receptor selectivity"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6298-0193","authenticated-orcid":false,"given":"Jiaqi","family":"Ma","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00mkhxb43","id-type":"ROR","asserted-by":"publisher"}],"name":"Harper Cancer Research Institute and the Department of Chemistry and Biochemistry, University of Notre Dame","place":["Notre Dame"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cory M.","family":"Ayres","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00mkhxb43","id-type":"ROR","asserted-by":"publisher"}],"name":"Harper Cancer Research Institute and the Department of Chemistry and Biochemistry, University of Notre Dame","place":["Notre Dame"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chad A.","family":"Brambley","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00mkhxb43","id-type":"ROR","asserted-by":"publisher"}],"name":"Harper Cancer Research Institute and the Department of Chemistry and Biochemistry, University of Notre Dame","place":["Notre Dame"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9532-8546","authenticated-orcid":false,"given":"Bassant","family":"Eldaly","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00mkhxb43","id-type":"ROR","asserted-by":"publisher"}],"name":"Harper Cancer Research Institute and the Department of Chemistry and Biochemistry, University of Notre Dame","place":["Notre Dame"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5114-1979","authenticated-orcid":false,"given":"W. W. J. Gihan","family":"Perera","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00mkhxb43","id-type":"ROR","asserted-by":"publisher"}],"name":"Harper Cancer Research Institute and the Department of Chemistry and Biochemistry, University of Notre Dame","place":["Notre Dame"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5975-281X","authenticated-orcid":false,"given":"James A.","family":"Lazar","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00mkhxb43","id-type":"ROR","asserted-by":"publisher"}],"name":"Harper Cancer Research Institute and the Department of Chemistry and Biochemistry, University of Notre Dame","place":["Notre Dame"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evgenii L.","family":"Kovrigin","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00mkhxb43","id-type":"ROR","asserted-by":"publisher"}],"name":"Harper Cancer Research Institute and the Department of Chemistry and Biochemistry, University of Notre Dame","place":["Notre Dame"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Smita S.","family":"Chandran","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02yrq0923","id-type":"ROR","asserted-by":"publisher"}],"name":"Immuno-Oncology Program, Memorial Sloan Kettering Cancer Center","place":["New York"]},{"id":[{"id":"https:\/\/ror.org\/02yrq0923","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Cellular Immunotherapy, Memorial Sloan Kettering Cancer Center","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher A.","family":"Klebanoff","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02yrq0923","id-type":"ROR","asserted-by":"publisher"}],"name":"Immuno-Oncology Program, Memorial Sloan Kettering Cancer Center","place":["New York"]},{"id":[{"id":"https:\/\/ror.org\/02yrq0923","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Cellular Immunotherapy, Memorial Sloan Kettering Cancer Center","place":["New York"]},{"id":[{"id":"https:\/\/ror.org\/05bnh6r87","id-type":"ROR","asserted-by":"publisher"}],"name":"Weill Cornell Medical College, Department of Medicine, Cornell University","place":["New York"]},{"id":[{"id":"https:\/\/ror.org\/02yrq0923","id-type":"ROR","asserted-by":"publisher"}],"name":"Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0864-0964","authenticated-orcid":false,"given":"Brian M.","family":"Baker","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00mkhxb43","id-type":"ROR","asserted-by":"publisher"}],"name":"Harper Cancer Research Institute and the Department of Chemistry and Biochemistry, University of Notre Dame","place":["Notre Dame"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,6,1]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-023-00809-z"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.141.2.502"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq998"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2172-9-1"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2018-213779"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/rap\/rkad087"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.humimm.2013.09.008"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1195271"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1042\/BST20220244"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2008.04.020"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature11147"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-02-072405"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/bmt.2011.56"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07109-w"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M410807200"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20030066"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1920570117"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-38573-8"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12977-015-0149-5"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20011644"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni1432"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2011.08.015"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01709"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2009.09.025"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1207896109"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20082136"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.27316"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2007.12.009"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00179"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.177.10.6804"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201445307"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep14928"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.202350683"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1080\/07391102.2017.1295884"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1915562116"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-01786-3"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-56004-8"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2018125118"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.490664"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1111\/febs.15278"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2024.5364"},{"key":"e_1_3_4_42_2","first-page":"D783","article-title":"Allele frequency net database (AFND) 2020 update: Gold-standard data classification, open access genotype data and new query tools","volume":"48","author":"Gonzalez-Galarza Faviel F.","year":"2019","unstructured":"Faviel F. Gonzalez-Galarza , Allele frequency net database (AFND) 2020 update: Gold-standard data classification, open access genotype data and new query tools. Nucleic Acids Res. 48, D783\u2013D788 (2019).","journal-title":"Nucleic Acids Res."},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-025-01009-x"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.0c00689"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jim.2016.02.016"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2022.102184"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.4c00534"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20090732"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10858-022-00411-2"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-59446-w"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1021\/ct100666v"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1002\/cti2.1422"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.202451079"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.10.6175"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiw471"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.3390\/biophysica1020015"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32811-1"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1010337"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.crstbi.2024.100148"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0198-8859(97)00175-4"},{"key":"e_1_3_4_61_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0232849"},{"key":"e_1_3_4_62_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.152.3.1213"},{"key":"e_1_3_4_63_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.143.4.1101"},{"key":"e_1_3_4_64_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.2.674"},{"key":"e_1_3_4_65_2","first-page":"1429","article-title":"Identifying coevolutionary patterns in human leukocyte antigen (HLA) molecules.","volume":"64","author":"Jiang X.","year":"2010","unstructured":"X. Jiang, M. A. Fares, Identifying coevolutionary patterns in human leukocyte antigen (HLA) molecules.. Evolution 64, 1429\u20131445 (2010).","journal-title":"Evolution"},{"key":"e_1_3_4_66_2","doi-asserted-by":"publisher","DOI":"10.1002\/bies.70126"},{"key":"e_1_3_4_67_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.09.074"},{"key":"e_1_3_4_68_2","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/298145"},{"key":"e_1_3_4_69_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2021.02.004"},{"key":"e_1_3_4_70_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00065"},{"key":"e_1_3_4_71_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20040217"},{"key":"e_1_3_4_72_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80080-1"},{"key":"e_1_3_4_73_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1491656"},{"key":"e_1_3_4_74_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00966"},{"key":"e_1_3_4_75_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00935"},{"key":"e_1_3_4_76_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1169377"},{"key":"e_1_3_4_77_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.6b00283"},{"key":"e_1_3_4_78_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2018.05.005"},{"key":"e_1_3_4_79_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abl5282"},{"key":"e_1_3_4_80_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.02.053"},{"key":"e_1_3_4_81_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.adx3162"},{"key":"e_1_3_4_82_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2300121"},{"key":"e_1_3_4_83_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2017.00002"},{"key":"e_1_3_4_84_2","doi-asserted-by":"crossref","unstructured":"J. Ma B. M. Baker Data for HLA micropolymorphisms confine neoantigen conformational adaptability and guide T cell receptor selectivity. Zenodo. https:\/\/doi.org\/10.5281\/zenodo.19664051. Deposited 20 April 2026.","DOI":"10.64898\/2025.12.22.696040"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2602949123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T19:34:35Z","timestamp":1780342475000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2602949123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,1]]},"references-count":84,"journal-issue":{"issue":"23","published-print":{"date-parts":[[2026,6,9]]}},"alternative-id":["10.1073\/pnas.2602949123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2602949123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,1]]},"assertion":[{"value":"2026-02-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-28","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-01","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2602949123"}}