{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T14:50:03Z","timestamp":1790866203377,"version":"4.1.0"},"reference-count":60,"publisher":"National Academy of Sciences","issue":"20","license":[{"start":{"date-parts":[[2024,5,6]],"date-time":"2024-05-06T00:00:00Z","timestamp":1714953600000},"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":["P01 AI118688"],"award-info":[{"award-number":["P01 AI118688"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017618","name":"HHS | NIH | NIDDK | Division of Diabetes, Endocrinology, and Metabolic Diseases","doi-asserted-by":"publisher","award":["R01 DK133443"],"award-info":[{"award-number":["R01 DK133443"]}],"id":[{"id":"10.13039\/100017618","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":[[2024,5,14]]},"abstract":"<jats:p>\n                    Insulin is a central autoantigen in the pathogenesis of T1D, and thymic epithelial cell expression of insulin under the control of the Autoimmune Regulator (\n                    <jats:italic>Aire<\/jats:italic>\n                    ) is thought to be a key component of maintaining tolerance to insulin. In spite of this general working model, direct detection of this thymic selection on insulin-specific T cells has been somewhat elusive. Here, we used a combination of highly sensitive T cell receptor transgenic models for detecting thymic selection and sorting and sequencing of Insulin-specific CD4+ T cells from Aire-deficient mice as a strategy to further define their selection. This analysis revealed a number of unique t cell receptor (TCR) clones in Aire-deficient hosts with high affinity for insulin\/major histocompatibility complex (MHC) ligands. We then modeled the thymic selection of one of these clones in Aire-deficient versus wild-type hosts and found that this model clone could escape thymic negative selection in the absence of thymic Aire. Together, these results suggest that thymic expression of insulin plays a key role in trimming and removing high-affinity insulin-specific T cells from the repertoire to help promote tolerance.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2320268121","type":"journal-article","created":{"date-parts":[[2024,5,6]],"date-time":"2024-05-06T15:00:32Z","timestamp":1715007632000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":9,"title":["Aire mediates tolerance to insulin through thymic trimming of high-affinity T cell clones"],"prefix":"10.1073","volume":"121","author":[{"given":"Jennifer A.","family":"Smith","sequence":"first","affiliation":[{"name":"Diabetes Center, University of California San Francisco, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin T. K.","family":"Yuen","sequence":"additional","affiliation":[{"name":"Diabetes Center, University of California San Francisco, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Whitney","family":"Purtha","sequence":"additional","affiliation":[{"name":"Diabetes Center, University of California San Francisco, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4119-2822","authenticated-orcid":false,"given":"Jared M.","family":"Balolong","sequence":"additional","affiliation":[{"name":"Diabetes Center, University of California San Francisco, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9685-741X","authenticated-orcid":false,"given":"Jonah D.","family":"Phipps","sequence":"additional","affiliation":[{"name":"Diabetes Center, University of California San Francisco, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances","family":"Crawford","sequence":"additional","affiliation":[{"name":"Department of Immunology and Genomic Medicine, National Jewish Health, Denver, CO 80206"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey A.","family":"Bluestone","sequence":"additional","affiliation":[{"name":"Sean N. Parker Autoimmune Research Laboratory, Diabetes Center, University of California, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5827-6240","authenticated-orcid":false,"given":"John W.","family":"Kappler","sequence":"additional","affiliation":[{"name":"Department of Immunology and Genomic Medicine, National Jewish Health, Denver, CO 80206"},{"name":"Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045"},{"name":"Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark S.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Diabetes Center, University of California San Francisco, San Francisco, CA 94143"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,5,6]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a007807"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.23.021704.115643"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1034\/j.1399-0039.2003.00152.x"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2007.11.005"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature03523"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0952-7915(98)80085-X"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1197-350"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0397-293"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.54.suppl_2.S18"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/gene.2009.108"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0397-289"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1075958"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1297-399"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1297-393"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.86.10.7884"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI34523"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.04.021"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.171645.113"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3246"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3247"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21346-6"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1006\/jaut.1997.0183"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1006\/jaut.1999.0282"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI89919"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830240820"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1006\/jaut.1994.1066"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.2337\/diab.46.7.1124"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/12465"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830250430"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1006\/jaut.2000.0369"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0020090"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80572-5"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1113954108"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.10.6051"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20111502"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20130582"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0341-6"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1850"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri3294"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1337.031"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.2337\/db11-1113"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2009.02.003"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.fcr.2004.04.003"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1222149110"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1715590115"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1716527115"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.2337\/db06-0058"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.6.2518"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.156.2.450"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.167.8.4311"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-1759(95)00124-S"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80405-7"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90730-E"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.2337\/db07-1129"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1006545107"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1097\/MED.0000000000000490"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.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Smith M. Anderson Data from \u201cInsulin-specific T cell sequencing.\u201d TCR raw sequence reads. NIH. http:\/\/www.ncbi.nlm.nih.gov\/bioproject\/PRJNA1082731. Deposited 1 March 2024."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2320268121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,23]],"date-time":"2024-05-23T10:27:20Z","timestamp":1716460040000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2320268121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,6]]},"references-count":60,"journal-issue":{"issue":"20","published-print":{"date-parts":[[2024,5,14]]}},"alternative-id":["10.1073\/pnas.2320268121"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2320268121","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,6]]},"assertion":[{"value":"2023-11-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-03-16","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-06","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2320268121"}}