{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T21:30:05Z","timestamp":1790371805273,"version":"4.1.0"},"reference-count":62,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2023,11,20]],"date-time":"2023-11-20T00:00:00Z","timestamp":1700438400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Gouvernement du Canada | Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PS 156104"],"award-info":[{"award-number":["PS 156104"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,1,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Highly self-reactive T cells are censored from the repertoire by both central and peripheral tolerance mechanisms upon receipt of high-affinity TCR signals. Clonal deletion is considered a major driver of central tolerance; however, other mechanisms such as induction of regulatory T cells and functional impairment have been described. An understanding of the interplay between these different central tolerance mechanisms is still lacking. We previously showed that impaired clonal deletion to a model tissue-restricted Ag did not compromise tolerance. In this study, we determined that murine T cells that failed clonal deletion were rendered functionally impaired in the thymus. Programmed cell death protein 1 (PD-1) was induced in the thymus and was required to establish cell-intrinsic tolerance to tissue-restricted Ag in CD8+ thymocytes independently of clonal deletion. In bone marrow chimeras, tolerance was not observed in PD-L1\u2013deficient recipients, but tolerance was largely maintained following adoptive transfer of tolerant thymocytes or T cells to PD-L1\u2013deficient recipients. However, CRISPR-mediated ablation of PD-1 in tolerant T cells resulted in broken tolerance, suggesting different PD-1 signaling requirements for establishing versus maintaining tolerance. Finally, we showed that chronic exposure to high-affinity Ag supported the long-term maintenance of tolerance. Taken together, our study identifies a critical role for PD-1 in establishing central tolerance in autoreactive T cells that escape clonal deletion. It also sheds light on potential mechanisms of action of anti\u2013PD-1 pathway immune checkpoint blockade and the development of immune-related adverse events.<\/jats:p>","DOI":"10.4049\/jimmunol.2200775","type":"journal-article","created":{"date-parts":[[2023,11,20]],"date-time":"2023-11-20T09:37:55Z","timestamp":1700473075000},"page":"271-283","source":"Crossref","is-referenced-by-count":7,"title":["Establishment of CD8+ T Cell Thymic Central Tolerance to Tissue-Restricted Antigen Requires PD-1"],"prefix":"10.1093","volume":"212","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3948-3444","authenticated-orcid":false,"given":"Julia F","family":"May","sequence":"first","affiliation":[{"name":"Department of Medical Microbiology and Immunology, University of Alberta , Edmonton, Alberta ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9429-9087","authenticated-orcid":false,"given":"Rees G","family":"Kelly","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, University of Alberta , Edmonton, Alberta ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6717-592X","authenticated-orcid":false,"given":"Alexander Y W","family":"Suen","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, University of Alberta , Edmonton, Alberta ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeongbee","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Alberta , Edmonton, Alberta ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeongwoo","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Alberta , Edmonton, Alberta ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1733-4237","authenticated-orcid":false,"given":"Colin C","family":"Anderson","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, University of Alberta , Edmonton, Alberta ,","place":["Canada"]},{"name":"Department of Surgery, University of Alberta , Edmonton, Alberta ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1450-7892","authenticated-orcid":false,"given":"Gina R","family":"Rayat","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Alberta , Edmonton, Alberta ,","place":["Canada"]},{"name":"Ray Rajotte Surgical-Medical Research Institute, AB Diabetes and Transplant Institutes, University of Alberta , Edmonton, Alberta ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0122-3746","authenticated-orcid":false,"given":"Troy A","family":"Baldwin","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, University of Alberta , Edmonton, Alberta ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,11,20]]},"reference":[{"key":"2025020405430433800_r1","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1038\/ni.2938","article-title":"The self-obsession of T cells: how TCR signaling thresholds affect fate \u201cdecisions\u201d and effector function","volume":"15","author":"Hogquist","year":"2014","journal-title":"Nat. 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