{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T05:52:24Z","timestamp":1773640344415,"version":"3.50.1"},"reference-count":52,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2013,12,4]],"date-time":"2013-12-04T00:00:00Z","timestamp":1386115200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Eur J Immunol"],"published-print":{"date-parts":[[2014,1]]},"abstract":"<jats:p>Thymic epithelial cells (<jats:styled-content style=\"fixed-case\">TEC<\/jats:styled-content>s) provide key instructive signals for <jats:styled-content style=\"fixed-case\">T<\/jats:styled-content>\u2010cell differentiation. Thymic cortical (c<jats:styled-content style=\"fixed-case\">TEC<\/jats:styled-content>s) and medullary (m<jats:styled-content style=\"fixed-case\">TEC<\/jats:styled-content>s) epithelial cells constitute two functionally distinct microenvironments for <jats:styled-content style=\"fixed-case\">T<\/jats:styled-content>\u2010cell development, which derive from a common bipotent <jats:styled-content style=\"fixed-case\">TEC<\/jats:styled-content> progenitor. While seminal studies have partially elucidated events downstream of bipotent <jats:styled-content style=\"fixed-case\">TEC<\/jats:styled-content>s in relation to the emergence of m<jats:styled-content style=\"fixed-case\">TEC<\/jats:styled-content>s and their progenitors, the control and timing of the emergence of the c<jats:styled-content style=\"fixed-case\">TEC<\/jats:styled-content> lineage, particularly in relation to that of m<jats:styled-content style=\"fixed-case\">TEC<\/jats:styled-content> progenitors, has remained elusive. In this review, we describe distinct models that explain c<jats:styled-content style=\"fixed-case\">TEC<\/jats:styled-content>\/m<jats:styled-content style=\"fixed-case\">TEC<\/jats:styled-content> lineage divergence from common bipotent progenitors. In particular, we summarize recent studies in mice providing evidence that m<jats:styled-content style=\"fixed-case\">TEC<\/jats:styled-content>s, including the auto\u2010immune regulator<jats:sup>+<\/jats:sup> subset, derive from progenitors initially endowed with phenotypic properties typically associated with the c<jats:styled-content style=\"fixed-case\">TEC<\/jats:styled-content> lineage. These observations support a novel \u201cserial progression\u201d model of <jats:styled-content style=\"fixed-case\">TEC<\/jats:styled-content> development, in which progenitors serially acquire c<jats:styled-content style=\"fixed-case\">TEC<\/jats:styled-content> lineage markers, prior to their commitment to the m<jats:styled-content style=\"fixed-case\">TEC<\/jats:styled-content> differentiation pathway. Gaining a better understanding of the phenotypic properties of early stages in <jats:styled-content style=\"fixed-case\">TEC<\/jats:styled-content> progenitor development should help in determining the mechanisms regulating c<jats:styled-content style=\"fixed-case\">TEC<\/jats:styled-content>\/m<jats:styled-content style=\"fixed-case\">TEC<\/jats:styled-content> lineage development, and in strategies aimed at thymus reconstitution involving <jats:styled-content style=\"fixed-case\">TEC<\/jats:styled-content> therapy.<\/jats:p>","DOI":"10.1002\/eji.201344110","type":"journal-article","created":{"date-parts":[[2013,11,11]],"date-time":"2013-11-11T06:40:39Z","timestamp":1384152039000},"page":"16-22","source":"Crossref","is-referenced-by-count":95,"title":["Serial progression of cortical and medullary thymic epithelial microenvironments"],"prefix":"10.1002","volume":"44","author":[{"given":"Nuno L.","family":"Alves","sequence":"first","affiliation":[{"name":"Infection and Immunity Unit Institute for Molecular and Cellular Biology University of Porto  Porto Portugal"}]},{"given":"Yousuke","family":"Takahama","sequence":"additional","affiliation":[{"name":"Division of Experimental Immunology Institute for Genome Research University of Tokushima  Tokushima Japan"}]},{"given":"Izumi","family":"Ohigashi","sequence":"additional","affiliation":[{"name":"Division of Experimental Immunology Institute for Genome Research University of Tokushima  Tokushima Japan"}]},{"given":"Ana R.","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Infection and Immunity Unit Institute for Molecular and Cellular Biology University of Porto  Porto Portugal"}]},{"given":"Song","family":"Baik","sequence":"additional","affiliation":[{"name":"Medical Research Council Centre for Immune Regulation Institute for Biomedical Research Medical School University of Birmingham  Birmingham UK"}]},{"given":"Graham","family":"Anderson","sequence":"additional","affiliation":[{"name":"Medical Research Council Centre for Immune Regulation Institute for Biomedical Research Medical School University of Birmingham  Birmingham UK"}]},{"given":"William E.","family":"Jenkinson","sequence":"additional","affiliation":[{"name":"Medical Research Council Centre for Immune Regulation Institute for Biomedical Research Medical School University of Birmingham  Birmingham UK"}]}],"member":"311","published-online":{"date-parts":[[2013,12,4]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri1781"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2012.03.005"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2009.07.010"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20080134"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0809559106"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1141915"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200839175"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.280.5362.450"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni723"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.25.022106.141532"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1075958"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20102327"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0804133"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-1759(01)00493-8"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.20.11822"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.182.1.130"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1118823109"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201041375"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1000601"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.12.8199"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200737131"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20062497"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1203203"},{"key":"e_1_2_9_25_1","doi-asserted-by":"crossref","first-page":"2453","DOI":"10.4049\/jimmunol.151.5.2453","article-title":"Medullary thymic epithelium expresses a ligand for CTLA4 in situ and in vitro","volume":"151","author":"Nelson A. 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