{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T10:25:48Z","timestamp":1772792748053,"version":"3.50.1"},"reference-count":54,"publisher":"Rockefeller University Press","issue":"10","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2004,11,15]]},"abstract":"<jats:p>It has been reported that the differentiation of CD4+CD25+ regulatory T cells (T reg cells) can be induced by agonist peptide\/major histocompatibility complex ligands in the thymus. Exploiting a transgenic mouse line wherein expression of a particular T cell epitope can be controlled temporally and quantitatively, we found that diversion of differentiating thymocytes into the FoxP3 T reg cell pathway by this agonist ligand was essentially nonexistent. However, CD4+CD25+ thymocytes were much less sensitive than their CD4+CD25\u2212 companions, by two to three orders of magnitude, to agonist-induced clonal deletion, such that their proportion increased, giving the false impression of induced differentiation. To account for these and prior observations, one can propose that differentiation along the CD4+CD25+ pathway is induced by cues other than recognition of self-agonist cues, which are poorly read by thymocytes, whose T cell receptors are conducive to selection toward the conventional CD4+CD25\u2212 lineage. Thus, selective survival, rather than induced differentiation, may explain the apparent enrichment observed here and in previous studies.<\/jats:p>","DOI":"10.1084\/jem.20041022","type":"journal-article","created":{"date-parts":[[2004,11,8]],"date-time":"2004-11-08T20:25:47Z","timestamp":1099945547000},"page":"1221-1230","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":167,"title":["Number of T Reg Cells That Differentiate Does Not Increase upon Encounter of Agonist Ligand on Thymic Epithelial Cells"],"prefix":"10.1084","volume":"200","author":[{"given":"Hisse-Martien","family":"van Santen","sequence":"first","affiliation":[{"name":"1Section on Immunology and Immunogenetics, Joslin Diabetes Center"},{"name":"2Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215"}]},{"given":"Christophe","family":"Benoist","sequence":"additional","affiliation":[{"name":"1Section on Immunology and Immunogenetics, Joslin Diabetes Center"},{"name":"2Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215"}]},{"given":"Diane","family":"Mathis","sequence":"additional","affiliation":[{"name":"1Section on Immunology and Immunogenetics, Joslin Diabetes Center"},{"name":"2Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215"}]}],"member":"291","published-online":{"date-parts":[[2004,11,8]]},"reference":[{"key":"2023072512264367500_BIB1","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/0092-8674(87)90568-X","volume":"49","year":"1987","journal-title":"Cell."},{"key":"2023072512264367500_BIB2","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1038\/333742a0","volume":"333","year":"1988","journal-title":"Nature."},{"key":"2023072512264367500_BIB3","first-page":"139","volume":"298","year":"2002","journal-title":"Science."},{"key":"2023072512264367500_BIB4","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1038\/ni0901-816","volume":"2","year":"2001","journal-title":"Nat. Immunol."},{"key":"2023072512264367500_BIB5","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/nri821","volume":"2","year":"2002","journal-title":"Nat. Rev. Immunol."},{"key":"2023072512264367500_BIB6","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/nri1027","volume":"3","year":"2003","journal-title":"Nat. Rev. Immunol."},{"key":"2023072512264367500_BIB7","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.4049\/jimmunol.155.3.1151","volume":"155","year":"1995","journal-title":"J. Immunol."},{"key":"2023072512264367500_BIB8","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1084\/jem.184.2.387","volume":"184","year":"1996","journal-title":"J. Exp. Med."},{"key":"2023072512264367500_BIB9","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1093\/intimm\/10.4.371","volume":"10","year":"1998","journal-title":"Int. Immunol."},{"key":"2023072512264367500_BIB10","doi-asserted-by":"crossref","first-page":"5317","DOI":"10.4049\/jimmunol.162.9.5317","volume":"162","year":"1999","journal-title":"J. Immunol."},{"key":"2023072512264367500_BIB11","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.4049\/jimmunol.167.3.1245","volume":"167","year":"2001","journal-title":"J. Immunol."},{"key":"2023072512264367500_BIB12","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1084\/jem.193.11.1303","volume":"193","year":"2001","journal-title":"J. Exp. Med."},{"key":"2023072512264367500_BIB13","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1084\/jem.193.11.1285","volume":"193","year":"2001","journal-title":"J. Exp. Med."},{"key":"2023072512264367500_BIB14","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1084\/jem.193.11.1295","volume":"193","year":"2001","journal-title":"J. Exp. Med."},{"key":"2023072512264367500_BIB15","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1002\/1521-4141(200104)31:4<1247::AID-IMMU1247>3.0.CO;2-M","volume":"31","year":"2001","journal-title":"Eur. J. Immunol."},{"key":"2023072512264367500_BIB16","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1002\/1521-4141(200104)31:4<1122::AID-IMMU1122>3.0.CO;2-P","volume":"31","year":"2001","journal-title":"Eur. J. Immunol."},{"key":"2023072512264367500_BIB17","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/ni904","volume":"4","year":"2003","journal-title":"Nat. Immunol."},{"key":"2023072512264367500_BIB18","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1126\/science.1079490","volume":"299","year":"2003","journal-title":"Science."},{"key":"2023072512264367500_BIB19","first-page":"337","volume":"4","year":"2003","journal-title":"Nat. Immunol."},{"key":"2023072512264367500_BIB20","first-page":"1379","volume":"138","year":"1991","journal-title":"Am. J. Pathol."},{"key":"2023072512264367500_BIB21","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1046\/j.1365-2249.2003.02217.x","volume":"133","year":"2003","journal-title":"Clin. Exp. Immunol."},{"key":"2023072512264367500_BIB22","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1097\/00002281-200307000-00010","volume":"15","year":"2003","journal-title":"Curr. Opin. Rheumatol."},{"key":"2023072512264367500_BIB23","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/83713","volume":"27","year":"2001","journal-title":"Nat. Genet."},{"key":"2023072512264367500_BIB24","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1038\/83707","volume":"27","year":"2001","journal-title":"Nat. Genet."},{"key":"2023072512264367500_BIB25","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1084\/jem.193.11.F41","volume":"193","year":"2001","journal-title":"J. Exp. Med."},{"key":"2023072512264367500_BIB26","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/86283","volume":"2","year":"2001","journal-title":"Nat. Immunol."},{"key":"2023072512264367500_BIB27","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1038\/ni816","volume":"3","year":"2002","journal-title":"Nat. Immunol."},{"key":"2023072512264367500_BIB28","doi-asserted-by":"crossref","first-page":"4399","DOI":"10.4049\/jimmunol.168.9.4399","volume":"168","year":"2002","journal-title":"J. Immunol."},{"key":"2023072512264367500_BIB29","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1084\/jem.20030315","volume":"198","year":"2003","journal-title":"J. Exp. Med."},{"key":"2023072512264367500_BIB30","doi-asserted-by":"crossref","first-page":"9302","DOI":"10.1073\/pnas.91.20.9302","volume":"91","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072512264367500_BIB31","doi-asserted-by":"crossref","first-page":"10933","DOI":"10.1073\/pnas.93.20.10933","volume":"93","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072512264367500_BIB32","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1038\/341746a0","volume":"341","year":"1989","journal-title":"Nature."},{"key":"2023072512264367500_BIB33","doi-asserted-by":"crossref","first-page":"3002","DOI":"10.4049\/jimmunol.137.9.3002","volume":"137","year":"1986","journal-title":"J. Immunol."},{"key":"2023072512264367500_BIB34","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1084\/jem.191.2.355","volume":"191","year":"2000","journal-title":"J. Exp. Med."},{"key":"2023072512264367500_BIB35","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/0092-8674(93)90081-Z","volume":"72","year":"1993","journal-title":"Cell."},{"key":"2023072512264367500_BIB36","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/316038a0","volume":"316","year":"1985","journal-title":"Nature."},{"key":"2023072512264367500_BIB37","doi-asserted-by":"crossref","first-page":"3355","DOI":"10.4049\/jimmunol.160.7.3355","volume":"160","year":"1998","journal-title":"J. Immunol."},{"key":"2023072512264367500_BIB38","doi-asserted-by":"crossref","first-page":"7499","DOI":"10.1073\/pnas.94.14.7499","volume":"94","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072512264367500_BIB39","doi-asserted-by":"crossref","first-page":"2598","DOI":"10.4049\/jimmunol.135.4.2598","volume":"135","year":"1985","journal-title":"J. Immunol."},{"key":"2023072512264367500_BIB40","doi-asserted-by":"crossref","first-page":"5547","DOI":"10.1073\/pnas.89.12.5547","volume":"89","year":"1992","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072512264367500_BIB41","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/ni759","volume":"3","year":"2002","journal-title":"Nat. Immunol."},{"key":"2023072512264367500_BIB42","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/S1074-7613(02)00280-7","volume":"16","year":"2002","journal-title":"Immunity."},{"key":"2023072512264367500_BIB43","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/ni743","volume":"3","year":"2002","journal-title":"Nat. Immunol."},{"key":"2023072512264367500_BIB44","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1093\/intimm\/10.12.1969","volume":"10","year":"1998","journal-title":"Int. Immunol."},{"key":"2023072512264367500_BIB45","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1084\/jem.188.2.287","volume":"188","year":"1998","journal-title":"J. Exp. Med."},{"key":"2023072512264367500_BIB46","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1084\/jem.20031137","volume":"199","year":"2004","journal-title":"J. Exp. Med."},{"key":"2023072512264367500_BIB47","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/S0167-5699(97)01055-4","volume":"18","year":"1997","journal-title":"Immunol. Today."},{"key":"2023072512264367500_BIB48","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1084\/jem.194.4.427","volume":"194","year":"2001","journal-title":"J. Exp. Med."},{"key":"2023072512264367500_BIB49","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/S0092-8674(00)81028-4","volume":"84","year":"1996","journal-title":"Cell."},{"key":"2023072512264367500_BIB50","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/S0092-8674(00)81905-4","volume":"88","year":"1997","journal-title":"Cell."},{"key":"2023072512264367500_BIB51","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1084\/jem.186.7.1149","volume":"186","year":"1997","journal-title":"J. Exp. Med."},{"key":"2023072512264367500_BIB52","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1182\/blood-2001-12-0276","volume":"100","year":"2002","journal-title":"Blood."},{"key":"2023072512264367500_BIB53","doi-asserted-by":"crossref","first-page":"6216","DOI":"10.1073\/pnas.94.12.6216","volume":"94","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072512264367500_BIB54","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/S0960-9822(99)80093-1","volume":"9","year":"1999","journal-title":"Curr. Biol."}],"container-title":["The Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/200\/10\/1221\/1713360\/jem200101221.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/200\/10\/1221\/1713360\/jem200101221.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T08:37:45Z","timestamp":1690274265000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/200\/10\/1221\/52506\/Number-of-T-Reg-Cells-That-Differentiate-Does-Not"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,11,8]]},"references-count":54,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2004,11,15]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20041022","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.1022340.253708","asserted-by":"object"},{"id-type":"doi","id":"10.3410\/f.1022340.260653","asserted-by":"object"}]},"ISSN":["1540-9538","0022-1007"],"issn-type":[{"value":"1540-9538","type":"electronic"},{"value":"0022-1007","type":"print"}],"subject":[],"published":{"date-parts":[[2004,11,8]]}}}