{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T14:28:40Z","timestamp":1775744920872,"version":"3.50.1"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2013,8,1]],"date-time":"2013-08-01T00:00:00Z","timestamp":1375315200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Thymic epithelial cells (TECs) help orchestrate thymopoiesis, and TEC differentiation relies on bidirectional interactions with thymocytes. Although the molecular mediators that stimulate medullary thymic epithelial cell (mTEC) maturation are partially elucidated, the signals that regulate cortical thymic epithelial cell (cTEC) homeostasis remain elusive. Using IL-7 reporter mice, we show that TECs coexpressing high levels of IL-7 (Il7YFP+ TECs) reside within a subset of CD205+Ly51+CD40low cTECs that coexpresses Dll4, Ccl25, Ccrl1, Ctsl, Psmb11, and Prss16 and segregates from CD80+CD40high mTECs expressing Tnfrsf11a, Ctss, and Aire. As the frequency of Il7YFP+ TECs gradually declines as mTEC development unfolds, we explored the relationship between Il7YFP+ TECs and mTECs. In thymic organotypic cultures, the thymocyte-induced reduction in Il7YFP+ TECs dissociates from the receptor activator of NF-\u03baB\u2013mediated differentiation of CD80+ mTECs. Still, Il7YFP+ TECs can generate some CD80+ mTECs in a stepwise differentiation process via YFP\u2212Ly51lowCD80low intermediates. Il7YFP+ TECs are sustained in Rag2\u2212\/\u2212 mice, even following in vivo anti-CD3\u03b5 treatment that mimics the process of pre-TCR \u03b2-selection of thymocytes to the double positive (DP) stage. Using Marilyn-Rag2\u2212\/\u2212 TCR transgenic, we find that positive selection into the CD4 lineage moderately reduces the frequency of Il7YFP+ TECs, whereas negative selection provokes a striking loss of Il7YFP+ TECs. These results imply that the strength of MHC\/peptide\u2013TCR interactions between TECs and thymocytes during selection constitutes a novel rheostat that controls the maintenance of IL-7\u2013expressing cTECs.<\/jats:p>","DOI":"10.4049\/jimmunol.1203042","type":"journal-article","created":{"date-parts":[[2013,6,22]],"date-time":"2013-06-22T01:53:34Z","timestamp":1371866014000},"page":"1200-1209","source":"Crossref","is-referenced-by-count":93,"title":["Thymocyte Selection Regulates the Homeostasis of IL-7\u2013Expressing Thymic Cortical Epithelial Cells In Vivo"],"prefix":"10.1093","volume":"191","author":[{"given":"Ana R","family":"Ribeiro","sequence":"first","affiliation":[{"name":"Infection and Immunity Unit, CAGE Laboratory, Institute for Molecular and Cellular Biology, University of Porto , 4150-180 Porto,","place":["Portugal"]},{"name":"Doctoral Program in Biomedical Sciences, Institute for Biomedical Sciences Abel Salazar, University of Porto , 4050-313 Porto,","place":["Portugal"]}]},{"given":"Pedro M","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Infection and Immunity Unit, CAGE Laboratory, Institute for Molecular and Cellular Biology, University of Porto , 4150-180 Porto,","place":["Portugal"]},{"name":"Doctoral Program in Biomedical Sciences, Institute for Biomedical Sciences Abel Salazar, University of Porto , 4050-313 Porto,","place":["Portugal"]}]},{"given":"Catarina","family":"Meireles","sequence":"additional","affiliation":[{"name":"Infection and Immunity Unit, CAGE Laboratory, Institute for Molecular and Cellular Biology, University of Porto , 4150-180 Porto,","place":["Portugal"]}]},{"given":"James P","family":"Di Santo","sequence":"additional","affiliation":[{"name":"Innate Immunity Unit, INSERM Unit 668, Institut Pasteur , 75724 Paris,","place":["France"]}]},{"given":"Nuno L","family":"Alves","sequence":"additional","affiliation":[{"name":"Infection and Immunity Unit, CAGE Laboratory, Institute for Molecular and Cellular Biology, University of Porto , 4150-180 Porto,","place":["Portugal"]}]}],"member":"286","published-online":{"date-parts":[[2013,8,1]]},"reference":[{"key":"2025032405114421100_r1","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1038\/nri2187","article-title":"Generating intrathymic microenvironments to establish T-cell tolerance","volume":"7","author":"Anderson","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"2025032405114421100_r2","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1038\/nri1781","article-title":"Journey through the thymus: stromal guides for T-cell development and selection","volume":"6","author":"Takahama","year":"2006","journal-title":"Nat. Rev. Immunol."},{"key":"2025032405114421100_r3","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1146\/annurev.immunol.23.021704.115601","article-title":"A central role for central tolerance","volume":"24","author":"Kyewski","year":"2006","journal-title":"Annu. Rev. Immunol."},{"key":"2025032405114421100_r4","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1038\/nature04850","article-title":"Formation of a functional thymus initiated by a postnatal epithelial progenitor cell","volume":"441","author":"Bleul","year":"2006","journal-title":"Nature"},{"key":"2025032405114421100_r5","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1038\/nature04813","article-title":"Clonal analysis reveals a common progenitor for thymic cortical and medullary epithelium","volume":"441","author":"Rossi","year":"2006","journal-title":"Nature"},{"key":"2025032405114421100_r6","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1002\/eji.1830210711","article-title":"Disorganization and restoration of thymic medullary epithelial cells in T cell receptor-negative scid mice: evidence that receptor-bearing lymphocytes influence maturation of the thymic microenvironment","volume":"21","author":"Shores","year":"1991","journal-title":"Eur. J. Immunol."},{"key":"2025032405114421100_r7","doi-asserted-by":"crossref","first-page":"2842","DOI":"10.4049\/jimmunol.169.6.2842","article-title":"Cutting edge: thymocyte-independent and thymocyte-dependent phases of epithelial patterning in the fetal thymus","volume":"169","author":"Klug","year":"2002","journal-title":"J. Immunol."},{"key":"2025032405114421100_r8","doi-asserted-by":"crossref","first-page":"11822","DOI":"10.1073\/pnas.95.20.11822","article-title":"Interdependence of cortical thymic epithelial cell differentiation and T-lineage commitment","volume":"95","author":"Klug","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032405114421100_r9","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.it.2012.03.005","article-title":"Thymic epithelial cells: working class heroes for T cell development and repertoire selection","volume":"33","author":"Anderson","year":"2012","journal-title":"Trends Immunol."},{"key":"2025032405114421100_r10","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1084\/jem.181.4.1519","article-title":"Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine","volume":"181","author":"von Freeden-Jeffry","year":"1995","journal-title":"J. Exp. Med."},{"key":"2025032405114421100_r11","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1111\/j.0105-2896.2005.00234.x","article-title":"Interleukin-7 receptor alpha (IL-7Ralpha) deficiency: cellular and molecular bases. Analysis of clinical, immunological, and molecular features in 16 novel patients","volume":"203","author":"Giliani","year":"2005","journal-title":"Immunol. Rev."},{"key":"2025032405114421100_r12","doi-asserted-by":"crossref","first-page":"7060","DOI":"10.4049\/jimmunol.1003907","article-title":"Genetic evidence for an evolutionarily conserved role of IL-7 signaling in T cell development of zebrafish","volume":"186","author":"Iwanami","year":"2011","journal-title":"J. Immunol."},{"key":"2025032405114421100_r13","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.1073\/pnas.0809559106","article-title":"Characterization of the thymic IL-7 niche in vivo","volume":"106","author":"Alves","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032405114421100_r14","doi-asserted-by":"crossref","first-page":"e7637","DOI":"10.1371\/journal.pone.0007637","article-title":"Visualization and identification of IL-7 producing cells in reporter mice","volume":"4","author":"Mazzucchelli","year":"2009","journal-title":"PLoS ONE"},{"key":"2025032405114421100_r15","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1002\/dvg.20497","article-title":"IL7-hCD25 and IL7-Cre BAC transgenic mouse lines: new tools for analysis of IL-7 expressing cells","volume":"47","author":"Repass","year":"2009","journal-title":"Genesis"},{"key":"2025032405114421100_r16","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.4049\/jimmunol.1200586","article-title":"Identification of IL-7-producing cells in primary and secondary lymphoid organs using IL-7-GFP knock-in mice","volume":"189","author":"Hara","year":"2012","journal-title":"J. Immunol."},{"key":"2025032405114421100_r17","doi-asserted-by":"crossref","first-page":"5949","DOI":"10.4049\/jimmunol.1000601","article-title":"Cutting edge: a thymocyte-thymic epithelial cell cross-talk dynamically regulates intrathymic IL-7 expression in vivo","volume":"184","author":"Alves","year":"2010","journal-title":"J. Immunol."},{"key":"2025032405114421100_r18","doi-asserted-by":"crossref","first-page":"8199","DOI":"10.4049\/jimmunol.181.12.8199","article-title":"Cutting edge: thymic crosstalk regulates delta-like 4 expression on cortical epithelial cells","volume":"181","author":"Fiorini","year":"2008","journal-title":"J. Immunol."},{"key":"2025032405114421100_r19","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/j.it.2009.07.010","article-title":"Thymic epithelial cells: the multi-tasking framework of the T cell \u201ccradle.\u201d","volume":"30","author":"Alves","year":"2009","journal-title":"Trends Immunol."},{"key":"2025032405114421100_r20","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1016\/0092-8674(92)90029-C","article-title":"RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement","volume":"68","author":"Shinkai","year":"1992","journal-title":"Cell"},{"key":"2025032405114421100_r21","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1038\/76917","article-title":"Gamma chain required for na\u00efve CD4+ T cell survival but not for antigen proliferation","volume":"1","author":"Lantz","year":"2000","journal-title":"Nat. Immunol."},{"key":"2025032405114421100_r22","doi-asserted-by":"crossref","first-page":"3463","DOI":"10.1073\/pnas.1118823109","article-title":"Regenerative capacity of adult cortical thymic epithelial cells","volume":"109","author":"Rode","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032405114421100_r23","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/S0022-1759(01)00493-8","article-title":"Analysis of thymic stromal cell populations using flow cytometry","volume":"260","author":"Gray","year":"2002","journal-title":"J. Immunol. Methods"},{"key":"2025032405114421100_r24","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1084\/jem.20062497","article-title":"RANK signals from CD4(+)3(-) inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla","volume":"204","author":"Rossi","year":"2007","journal-title":"J. Exp. Med."},{"key":"2025032405114421100_r25","doi-asserted-by":"crossref","first-page":"11401","DOI":"10.1073\/pnas.90.23.11401","article-title":"Restoration of early thymocyte differentiation in T-cell receptor beta-chain-deficient mutant mice by transmembrane signaling through CD3 epsilon","volume":"90","author":"Levelt","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032405114421100_r26","doi-asserted-by":"crossref","first-page":"130","DOI":"10.4049\/jimmunol.182.1.130","article-title":"Checkpoints in the development of thymic cortical epithelial cells","volume":"182","author":"Shakib","year":"2009","journal-title":"J. Immunol."},{"key":"2025032405114421100_r27","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1084\/jem.20011904","article-title":"Cathepsin L regulates CD4+ T cell selection independently of its effect on invariant chain: a role in the generation of positively selecting peptide ligands","volume":"195","author":"Honey","year":"2002","journal-title":"J. Exp. Med."},{"key":"2025032405114421100_r28","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/j.immuni.2008.06.018","article-title":"The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator","volume":"29","author":"Hikosaka","year":"2008","journal-title":"Immunity"},{"key":"2025032405114421100_r29","doi-asserted-by":"crossref","first-page":"5047","DOI":"10.4049\/jimmunol.1003533","article-title":"Lymphotoxin signal promotes thymic organogenesis by eliciting RANK expression in the embryonic thymic stroma","volume":"186","author":"Mouri","year":"2011","journal-title":"J. Immunol."},{"key":"2025032405114421100_r30","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1084\/jem.20030794","article-title":"Thymic medullary epithelial cell differentiation, thymocyte emigration, and the control of autoimmunity require lympho-epithelial cross talk via LTbetaR","volume":"198","author":"Boehm","year":"2003","journal-title":"J. Exp. Med."},{"key":"2025032405114421100_r31","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.immuni.2008.08.007","article-title":"Autoantigen-specific interactions with CD4+ thymocytes control mature medullary thymic epithelial cell cellularity","volume":"29","author":"Irla","year":"2008","journal-title":"Immunity"},{"key":"2025032405114421100_r32","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/j.immuni.2008.06.015","article-title":"The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance","volume":"29","author":"Akiyama","year":"2008","journal-title":"Immunity"},{"key":"2025032405114421100_r33","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1038\/nri1636","article-title":"Unique features of the pre-T-cell receptor alpha-chain: not just a surrogate","volume":"5","author":"von Boehmer","year":"2005","journal-title":"Nat. Rev. Immunol."},{"key":"2025032405114421100_r34","doi-asserted-by":"crossref","first-page":"3777","DOI":"10.1182\/blood-2006-02-004531","article-title":"Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells","volume":"108","author":"Gray","year":"2006","journal-title":"Blood"},{"key":"2025032405114421100_r35","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1002\/eji.201041375","article-title":"Ontogeny of thymic cortical epithelial cells expressing the thymoproteasome subunit \u03b25t","volume":"41","author":"Ripen","year":"2011","journal-title":"Eur. J. Immunol."},{"key":"2025032405114421100_r36","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1002\/eji.201243209","article-title":"Generation of both cortical and Aire(+) medullary thymic epithelial compartments from CD205(+) progenitors","volume":"43","author":"Baik","year":"2013","journal-title":"Eur. J. Immunol."},{"key":"2025032405114421100_r37","doi-asserted-by":"crossref","first-page":"2395","DOI":"10.1002\/eji.200939501","article-title":"Absence of thymus crosstalk in the fetus does not preclude hematopoietic induction of a functional thymus in the adult","volume":"39","author":"Roberts","year":"2009","journal-title":"Eur. J. Immunol."},{"key":"2025032405114421100_r38","doi-asserted-by":"crossref","first-page":"1976","DOI":"10.4049\/jimmunol.165.4.1976","article-title":"Normal thymic architecture and negative selection are associated with Aire expression, the gene defective in the autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)","volume":"165","author":"Zuklys","year":"2000","journal-title":"J. Immunol."},{"key":"2025032405114421100_r39","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1242\/dev.127.8.1583","article-title":"Stepwise development of thymic microenvironments in vivo is regulated by thymocyte subsets","volume":"127","author":"van Ewijk","year":"2000","journal-title":"Development"},{"key":"2025032405114421100_r40","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1182\/blood-2012-01-406827","article-title":"Anti-CD3\u03b5 mAb improves thymic architecture and prevents autoimmune manifestations in a mouse model of Omenn syndrome: therapeutic implications","volume":"120","author":"Marrella","year":"2012","journal-title":"Blood"},{"key":"2025032405114421100_r41","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1002\/eji.200425675","article-title":"Thymic cortical epithelium induces self tolerance","volume":"35","author":"Goldman","year":"2005","journal-title":"Eur. J. Immunol."},{"key":"2025032405114421100_r42","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1007\/s00281-008-0137-0","article-title":"Central tolerance: what have we learned from mice?","volume":"30","author":"McCaughtry","year":"2008","journal-title":"Semin. Immunopathol."},{"key":"2025032405114421100_r43","doi-asserted-by":"crossref","first-page":"4679","DOI":"10.1073\/pnas.1217532110","article-title":"Murine thymic selection quantified using a unique method to capture deleted T cells","volume":"110","author":"Stritesky","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/191\/3\/1200\/62509922\/1203042.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/191\/3\/1200\/62509922\/1203042.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T23:14:44Z","timestamp":1742858084000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/191\/3\/1200\/7991047"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,8,1]]},"references-count":43,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2013,8,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1203042","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2013,8]]},"published":{"date-parts":[[2013,8,1]]}}}