{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:03:26Z","timestamp":1753891406554,"version":"3.41.2"},"reference-count":100,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,5,25]],"date-time":"2022-05-25T00:00:00Z","timestamp":1653436800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>CD4<jats:sup>+<\/jats:sup>T cell responses to self-antigens are pivotal for immunological self-tolerance. Activation of Foxp3<jats:sup>\u2013<\/jats:sup>T-conventional (T-conv) cells can precipitate autoimmune disease, whereas activation of Foxp3<jats:sup>+<\/jats:sup>T-regulatory (T-reg) cells is essential to prevent autoimmune disease. This distinction indicates the importance of the thymus in controlling the differentiation of self-reactive CD4<jats:sup>+<\/jats:sup>T cells. Thymocytes and thymic antigen-presenting cells (APC) depend on each other for normal maturation and differentiation. In this Hypothesis and Theory article, we propose this mutual dependence dictates which self-antigens induce T-reg cell development in the thymic medulla. We postulate self-reactive CD4<jats:sup>+<\/jats:sup>CD8<jats:sup>\u2013<\/jats:sup>thymocytes deliver signals that stabilize and amplify the presentation of their cognate self-antigen by APC in the thymic medulla, thereby seeding a niche for the development of T-reg cells specific for the same self-antigen. By limiting the number of antigen-specific CD4<jats:sup>+<\/jats:sup>thymocytes in the medulla, thymocyte deletion in the cortex may impede the formation of medullary T-reg niches containing certain self-antigens. Susceptibility to autoimmune disease may arise from cortical deletion creating a \u201chole\u201d in the self-antigen repertoire recognized by T-reg cells.<\/jats:p>","DOI":"10.3389\/fimmu.2022.892498","type":"journal-article","created":{"date-parts":[[2022,5,25]],"date-time":"2022-05-25T04:50:59Z","timestamp":1653454259000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["How Thymocyte Deletion in the Cortex May Curtail Antigen-Specific T-Regulatory Cell Development in the Medulla"],"prefix":"10.3389","volume":"13","author":[{"given":"Chenglong","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen 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