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To undergo central tolerance, thymocytes must enter the medulla to test their T-cell receptors (TCRs) for autoreactivity against the diverse self-antigens displayed by antigen-presenting cells (APCs). While CCR7 is known to promote thymocyte medullary entry and negative selection, our previous studies implicate CCR4 in these processes, raising the question of whether CCR4 and CCR7 play distinct or redundant roles in central tolerance. Here, synchronized positive selection assays, two-photon time-lapse microscopy, and quantification of TCR-signaled apoptotic thymocytes, demonstrate that CCR4 and CCR7 promote medullary accumulation and central tolerance of distinct post-positive selection thymocyte subsets in mice. CCR4 is upregulated within hours of positive selection signaling and promotes medullary entry and clonal deletion of immature post-positive selection thymocytes. In contrast, CCR7 is expressed several days later and is required for medullary localization and negative selection of mature thymocytes. In addition, CCR4 and CCR7 differentially enforce self-tolerance, with CCR4 enforcing tolerance to self-antigens presented by activated APCs, which express CCR4 ligands. Our findings show that CCR7 expression is not synonymous with medullary localization and support a revised model of central tolerance in which CCR4 and CCR7 promote early and late stages of negative selection, respectively, via interactions with distinct APC subsets.<\/jats:p>","DOI":"10.7554\/elife.80443","type":"journal-article","created":{"date-parts":[[2023,6,2]],"date-time":"2023-06-02T10:01:22Z","timestamp":1685700082000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.80443","source":"Crossref","is-referenced-by-count":22,"title":["CCR4 and CCR7 differentially regulate thymocyte localization with distinct outcomes for central tolerance"],"prefix":"10.7554","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1893-9046","authenticated-orcid":true,"given":"Yu","family":"Li","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00hj54h04","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular Biosciences, The University of Texas at Austin","place":["Austin, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3127-7095","authenticated-orcid":true,"given":"Pablo","family":"Guaman Tipan","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00hj54h04","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular Biosciences, The University of Texas at Austin","place":["Austin, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilary J","family":"Selden","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00hj54h04","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular Biosciences, The University of Texas at Austin","place":["Austin, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9478-7518","authenticated-orcid":true,"given":"Jayashree","family":"Srinivasan","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00hj54h04","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular Biosciences, The University of Texas at Austin","place":["Austin, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura P","family":"Hale","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00py81415","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pathology, Duke University","place":["Durham, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1697-1755","authenticated-orcid":true,"given":"Lauren IR","family":"Ehrlich","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00hj54h04","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular Biosciences, The University of Texas at Austin","place":["Austin, United States"]},{"id":[{"id":"https:\/\/ror.org\/00hj54h04","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Oncology, LIVESTRONG Cancer Institutes, The University of Texas at Austin Dell Medical School","place":["Austin, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2023,6,2]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1146\/annurev-immunol-051116-052320","article-title":"Thymic epithelial cells","volume":"35","author":"Abramson","year":"2017","journal-title":"Annual Review of Immunology"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"1503","DOI":"10.1084\/jem.186.9.1503","article-title":"Specific activation of the cysteine protease CPP32 during the negative selection of T cells in the thymus","volume":"186","author":"Alam","year":"1997","journal-title":"The Journal of Experimental Medicine"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"1395","DOI":"10.1126\/science.1075958","article-title":"Projection of an immunological self shadow within the thymus by the Aire protein","volume":"298","author":"Anderson","year":"2002","journal-title":"Science"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1038\/nri.2016.9","article-title":"AIRE expands: new roles in immune tolerance and beyond","volume":"16","author":"Anderson","year":"2016","journal-title":"Nature Reviews. 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