{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T13:51:03Z","timestamp":1789480263840,"version":"build-2803163510"},"reference-count":90,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2022,5,13]],"date-time":"2022-05-13T00:00:00Z","timestamp":1652400000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>One of the earliest hallmarks of immune aging is thymus involution, which not only reduces the number of newly generated and exported T cells, but also alters the composition and organization of the thymus microenvironment. Thymic T\u2010cell export continues into adulthood, yet the impact of thymus involution on the quality of newly generated T\u2010cell clones is not well established. Notably, the number and proportion of medullary thymic epithelial cells (mTECs) and expression of tissue\u2010restricted antigens (TRAs) decline with age, suggesting the involuting thymus may not promote efficient central tolerance. Here, we demonstrate that the middle\u2010aged thymic environment does not support rapid motility of medullary thymocytes, potentially diminishing their ability to scan antigen presenting cells (APCs) that display the diverse self\u2010antigens that induce central tolerance. Consistent with this possibility, thymic slice assays reveal that the middle\u2010aged thymic environment does not support efficient negative selection or regulatory T\u2010cell (Treg) induction of thymocytes responsive to either TRAs or ubiquitous self\u2010antigens. This decline in central tolerance is not universal, but instead impacts lower\u2010avidity self\u2010antigens that are either less abundant or bind to TCRs with moderate affinities. Additionally, the decline in thymic tolerance by middle age is accompanied by both a reduction in mTECs and hematopoietic APC subsets that cooperate to drive central tolerance. Thus, age\u2010associated changes in the thymic environment result in impaired central tolerance against moderate\u2010avidity self\u2010antigens, potentially resulting in export of increasingly autoreactive naive T cells, with a deficit of Treg counterparts by middle age.<\/jats:p>","DOI":"10.1111\/acel.13624","type":"journal-article","created":{"date-parts":[[2022,5,13]],"date-time":"2022-05-13T17:19:58Z","timestamp":1652462398000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Central tolerance is impaired in the middle\u2010aged thymic environment"],"prefix":"10.1111","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0398-9988","authenticated-orcid":false,"given":"Jessica N.","family":"Lancaster","sequence":"first","affiliation":[{"name":"Department of Molecular Biosciences The University of Texas at Austin  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damaris E.","family":"Keatinge\u2010Clay","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences The University of Texas at Austin  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayashree","family":"Srinivasan","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences The University of Texas at Austin  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences The University of Texas at Austin  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilary J.","family":"Selden","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences The University of Texas at Austin  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seohee","family":"Nam","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences The University of Texas at Austin  Austin Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen R.","family":"Richie","sequence":"additional","affiliation":[{"name":"Department of Epigenetics and Molecular Carcinogenesis The University of Texas MD Anderson Cancer Center  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1697-1755","authenticated-orcid":false,"given":"Lauren I. 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