{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T22:01:32Z","timestamp":1773871292974,"version":"3.50.1"},"reference-count":35,"publisher":"Rockefeller University Press","issue":"6","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2009,6,8]]},"abstract":"<jats:p>Invariant natural killer T (iNKT) cells constitute a distinct subset of T lymphocytes exhibiting important immune-regulatory functions. Although various steps of their differentiation have been well characterized, the factors controlling their development remain poorly documented. Here, we show that TGF-\u03b2 controls the differentiation program of iNKT cells. We demonstrate that TGF-\u03b2 signaling carefully and specifically orchestrates several steps of iNKT cell development. In vivo, this multifaceted role of TGF-\u03b2 involves the concerted action of different pathways of TGF-\u03b2 signaling. Whereas the Tif-1\u03b3 branch controls lineage expansion, the Smad4 branch maintains the maturation stage that is initially repressed by a Tif-1\u03b3\/Smad4-independent branch. Thus, these three different branches of TGF-\u03b2 signaling function in concert as complementary effectors, allowing TGF-\u03b2 to fine tune the iNKT cell differentiation program.<\/jats:p>","DOI":"10.1084\/jem.20090127","type":"journal-article","created":{"date-parts":[[2009,5,19]],"date-time":"2009-05-19T01:10:42Z","timestamp":1242695442000},"page":"1365-1378","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":79,"title":["iNKT cell development is orchestrated by different branches of TGF-\u03b2 signaling"],"prefix":"10.1084","volume":"206","author":[{"given":"Jean-Marc","family":"Doisne","sequence":"first","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM), U561\/Groupe AVENIR, H\u00f4pital Cochin St Vincent de Paul, Universit\u00e9 Descartes, Paris F-75014, France 1"}]},{"given":"Laurent","family":"Bartholin","sequence":"additional","affiliation":[{"name":"INSERM, U590, IFR62, Lyon, F-69008, France 2"},{"name":"Universit\u00e9 Lyon, Lyon, F-69003, France 6"},{"name":"Centre L\u00e9on B\u00e9rard, Lyon, F-69008, France 7"},{"name":"INSERM, U590\/Groupe AVENIR, Lyon, F-69008, France 9"}]},{"given":"Kai-Ping","family":"Yan","sequence":"additional","affiliation":[{"name":"Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire, Illkirch, F-67404, France 4"}]},{"given":"C\u00e9line N.","family":"Garcia","sequence":"additional","affiliation":[{"name":"INSERM, U758, IFR128, Lyon, F-69007, France 3"},{"name":"Universit\u00e9 Lyon, Lyon, F-69003, France 6"},{"name":"Ecole Normale Superieure de Lyon, Lyon, F-69007, France 8"}]},{"given":"Nadia","family":"Duarte","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM), U561\/Groupe AVENIR, H\u00f4pital Cochin St Vincent de Paul, Universit\u00e9 Descartes, Paris F-75014, France 1"}]},{"given":"Jean-Beno\u00eet","family":"Le Luduec","sequence":"additional","affiliation":[{"name":"INSERM U851 IFR128, Lyon, F-69007, France 5"},{"name":"Universit\u00e9 Lyon, Lyon, F-69003, France 6"}]},{"given":"David","family":"Vincent","sequence":"additional","affiliation":[{"name":"INSERM, U590, IFR62, Lyon, F-69008, France 2"},{"name":"Universit\u00e9 Lyon, Lyon, F-69003, France 6"},{"name":"Centre L\u00e9on B\u00e9rard, Lyon, F-69008, France 7"},{"name":"INSERM, U590\/Groupe AVENIR, Lyon, F-69008, France 9"}]},{"given":"Farhan","family":"Cyprian","sequence":"additional","affiliation":[{"name":"INSERM, U758, IFR128, Lyon, F-69007, France 3"},{"name":"Universit\u00e9 Lyon, Lyon, F-69003, France 6"},{"name":"Ecole Normale Superieure de Lyon, Lyon, F-69007, France 8"}]},{"given":"Branka","family":"Horvat","sequence":"additional","affiliation":[{"name":"INSERM, U758, IFR128, Lyon, F-69007, France 3"},{"name":"Universit\u00e9 Lyon, Lyon, F-69003, France 6"},{"name":"Ecole Normale Superieure de Lyon, Lyon, F-69007, France 8"}]},{"given":"Sylvie","family":"Martel","sequence":"additional","affiliation":[{"name":"INSERM, U590, IFR62, Lyon, F-69008, France 2"},{"name":"Universit\u00e9 Lyon, Lyon, F-69003, France 6"},{"name":"Centre L\u00e9on B\u00e9rard, Lyon, F-69008, France 7"},{"name":"INSERM, U590\/Groupe AVENIR, Lyon, F-69008, France 9"}]},{"given":"Ruth","family":"Rimokh","sequence":"additional","affiliation":[{"name":"INSERM, U590, IFR62, Lyon, F-69008, France 2"},{"name":"Universit\u00e9 Lyon, Lyon, F-69003, France 6"},{"name":"Centre L\u00e9on B\u00e9rard, Lyon, F-69008, France 7"}]},{"given":"R\u00e9gine","family":"Losson","sequence":"additional","affiliation":[{"name":"Institut de G\u00e9n\u00e9tique et de Biologie Mol\u00e9culaire et Cellulaire, Illkirch, F-67404, France 4"}]},{"given":"Kamel","family":"Benlagha","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM), U561\/Groupe AVENIR, H\u00f4pital Cochin St Vincent de Paul, Universit\u00e9 Descartes, Paris F-75014, France 1"}]},{"given":"Julien C.","family":"Marie","sequence":"additional","affiliation":[{"name":"INSERM, U758, IFR128, Lyon, F-69007, France 3"},{"name":"Universit\u00e9 Lyon, Lyon, F-69003, France 6"},{"name":"Ecole Normale Superieure de Lyon, Lyon, F-69007, France 8"}]}],"member":"291","published-online":{"date-parts":[[2009,5,18]]},"reference":[{"key":"2023072920152811200_bib1","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/nri854","article-title":"The unconventional lifestyle of NKT cells","volume":"2","author":"Kronenberg","year":"2002","journal-title":"Nat. Rev. Immunol."},{"key":"2023072920152811200_bib2","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1038\/nature03725","article-title":"Regulation of immunity by self-reactive T cells","volume":"435","author":"Kronenberg","year":"2005","journal-title":"Nature."},{"key":"2023072920152811200_bib3","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/nri1309","article-title":"NKT cells: what's in a name?","volume":"4","author":"Godfrey","year":"2004","journal-title":"Nat. Rev. Immunol."},{"key":"2023072920152811200_bib4","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1146\/annurev.immunol.23.021704.115742","article-title":"Toward an understanding of NKT cell biology: progress and paradoxes","volume":"23","author":"Kronenberg","year":"2005","journal-title":"Annu. Rev. Immunol."},{"key":"2023072920152811200_bib5","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1146\/annurev.immunol.25.022106.141711","article-title":"The biology of NKT cells","volume":"25","author":"Bendelac","year":"2007","journal-title":"Annu. Rev. Immunol."},{"key":"2023072920152811200_bib6","doi-asserted-by":"crossref","first-page":"3762","DOI":"10.4049\/jimmunol.175.6.3762","article-title":"The influence of CD1d in postselection NKT cell maturation and homeostasis","volume":"175","author":"McNab","year":"2005","journal-title":"J. Immunol."},{"key":"2023072920152811200_bib7","doi-asserted-by":"crossref","first-page":"4059","DOI":"10.4049\/jimmunol.176.7.4059","article-title":"Long-term retention of mature NK1.1+ NKT cells in the thymus","volume":"176","author":"Berzins","year":"2006","journal-title":"J. Immunol."},{"key":"2023072920152811200_bib8","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/S1074-7613(00)80664-0","article-title":"IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation","volume":"9","author":"Lodolce","year":"1998","journal-title":"Immunity."},{"key":"2023072920152811200_bib9","doi-asserted-by":"crossref","first-page":"5931","DOI":"10.4049\/jimmunol.159.12.5931","article-title":"Role for IL-15\/IL-15 receptor beta-chain in natural killer 1.1+ T cell receptor-alpha beta+ cell development","volume":"159","author":"Ohteki","year":"1997","journal-title":"J. Immunol."},{"key":"2023072920152811200_bib10","doi-asserted-by":"crossref","first-page":"7439","DOI":"10.1073\/pnas.96.13.7439","article-title":"Induction of differentiation of pre-NKT cells to mature Valpha14 NKT cells by granulocyte\/macrophage colony-stimulating factor","volume":"96","author":"Sato","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072920152811200_bib11","doi-asserted-by":"crossref","first-page":"671","DOI":"10.4049\/jimmunol.165.2.671","article-title":"Membrane lymphotoxin is required for the development of different subpopulations of NK T cells","volume":"165","author":"Elewaut","year":"2000","journal-title":"J. Immunol."},{"key":"2023072920152811200_bib12","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/j.immuni.2006.06.017","article-title":"Granulocyte-macrophage colony-stimulating factor regulates effector differentiation of invariant natural killer T cells during thymic ontogeny","volume":"25","author":"Bezbradica","year":"2006","journal-title":"Immunity."},{"key":"2023072920152811200_bib13","doi-asserted-by":"crossref","first-page":"9160","DOI":"10.1073\/pnas.0508892103","article-title":"A unique lymphotoxin {alpha}beta-dependent pathway regulates thymic emigration of V{alpha}14 invariant natural killer T cells","volume":"103","author":"Franki","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072920152811200_bib14","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/j.immuni.2006.07.011","article-title":"Transforming growth factor-beta controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms","volume":"25","author":"Li","year":"2006","journal-title":"Immunity."},{"key":"2023072920152811200_bib15","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.immuni.2006.07.012","article-title":"Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-beta receptor","volume":"25","author":"Marie","year":"2006","journal-title":"Immunity."},{"key":"2023072920152811200_bib16","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/nature02006","article-title":"Smad-dependent and Smad-independent pathways in TGF-beta family signalling","volume":"425","author":"Derynck","year":"2003","journal-title":"Nature."},{"key":"2023072920152811200_bib17","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1016\/j.cell.2006.03.045","article-title":"Hematopoiesis controlled by distinct TIF1gamma and Smad4 branches of the TGFbeta pathway","volume":"125","author":"He","year":"2006","journal-title":"Cell."},{"key":"2023072920152811200_bib18","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.cell.2005.01.033","article-title":"Germ-layer specification and control of cell growth by Ectodermin, a Smad4 ubiquitin ligase","volume":"121","author":"Dupont","year":"2005","journal-title":"Cell."},{"key":"2023072920152811200_bib19","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1038\/ni.1607","article-title":"A critical function for TGF-beta signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells","volume":"9","author":"Liu","year":"2008","journal-title":"Nat. Immunol."},{"key":"2023072920152811200_bib20","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1084\/jem.20042276","article-title":"TGF-\u03b21 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells","volume":"201","author":"Marie","year":"2005","journal-title":"J. Exp. Med."},{"key":"2023072920152811200_bib21","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1002\/dvg.20425","article-title":"Generation of mice with conditionally activated transforming growth factor beta signaling through the TbetaRI\/ALK5 receptor","volume":"46","author":"Bartholin","year":"2008","journal-title":"Genesis."},{"key":"2023072920152811200_bib22","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/j.cell.2008.07.025","article-title":"TGF-beta: a master of all T cell trades","volume":"134","author":"Li","year":"2008","journal-title":"Cell."},{"key":"2023072920152811200_bib23","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1111\/j.1600-065X.1995.tb00095.x","article-title":"Role of the common cytokine receptor gamma chain in cytokine signaling and lymphoid development","volume":"148","author":"Leonard","year":"1995","journal-title":"Immunol. Rev."},{"key":"2023072920152811200_bib24","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1038\/ni837","article-title":"Homeostasis of V alpha 14i NKT cells","volume":"3","author":"Matsuda","year":"2002","journal-title":"Nat. Immunol."},{"key":"2023072920152811200_bib25","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1126\/science.1069017","article-title":"A thymic precursor to the NK T cell lineage","volume":"296","author":"Benlagha","year":"2002","journal-title":"Science."},{"key":"2023072920152811200_bib26","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1016\/S1074-7613(04)00076-7","article-title":"T-bet regulates the terminal maturation and homeostasis of NK and Valpha14i NKT cells","volume":"20","author":"Townsend","year":"2004","journal-title":"Immunity."},{"key":"2023072920152811200_bib27","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.immuni.2008.05.007","article-title":"Molecular antagonism and plasticity of regulatory and inflammatory T cell programs","volume":"29","author":"Yang","year":"2008","journal-title":"Immunity."},{"key":"2023072920152811200_bib28","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/j.coi.2008.03.018","article-title":"CD1d-restricted iNKT cells, the \u2018Swiss-army knife\u2019 of the immune system","volume":"20","author":"Matsuda","year":"2008","journal-title":"Curr. Opin. Immunol."},{"key":"2023072920152811200_bib29","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1084\/jem.20011544","article-title":"A natural killer T (NKT) cell developmental pathway involving a thymus-dependent NK1.1\u2212CD4+ CD1d-dependent precursor stage","volume":"195","author":"Pellicci","year":"2002","journal-title":"J. Exp. Med."},{"key":"2023072920152811200_bib30","doi-asserted-by":"crossref","first-page":"E237","DOI":"10.1371\/journal.pbio.0020237","article-title":"The zebrafish moonshine gene encodes transcriptional intermediary factor 1gamma, an essential regulator of hematopoiesis","volume":"2","author":"Ransom","year":"2004","journal-title":"PLoS Biol."},{"key":"2023072920152811200_bib31","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1146\/annurev.immunol.16.1.137","article-title":"Regulation of immune responses by TGF-beta","volume":"16","author":"Letterio","year":"1998","journal-title":"Annu. Rev. Immunol."},{"key":"2023072920152811200_bib32","doi-asserted-by":"crossref","first-page":"2797","DOI":"10.1182\/blood-2005-08-3103","article-title":"T-bet concomitantly controls migration, survival, and effector functions during the development of Valpha14i NKT cells","volume":"107","author":"Matsuda","year":"2006","journal-title":"Blood."},{"key":"2023072920152811200_bib33","doi-asserted-by":"crossref","first-page":"3283","DOI":"10.1016\/j.molimm.2007.02.024","article-title":"TGF-beta 1 inhibition of IFN-gamma-induced signaling and Th1 gene expression in CD4+ T cells is Smad3 independent but MAP kinase dependent","volume":"44","author":"Park","year":"2007","journal-title":"Mol. Immunol."},{"key":"2023072920152811200_bib34","doi-asserted-by":"crossref","first-page":"5742","DOI":"10.1038\/sj.onc.1208928","article-title":"Crosstalk mechanisms between the mitogen-activated protein kinase pathways and Smad signaling downstream of TGF-beta: implications for carcinogenesis","volume":"24","author":"Javelaud","year":"2005","journal-title":"Oncogene."},{"key":"2023072920152811200_bib35","doi-asserted-by":"crossref","DOI":"10.1186\/gb-2002-3-7-research0034","article-title":"Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes","volume":"3","author":"Vandesompele","year":"2002","journal-title":"Genome Biol."}],"container-title":["Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/206\/6\/1365\/1910220\/jem_20090127.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/206\/6\/1365\/1910220\/jem_20090127.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,29]],"date-time":"2023-07-29T20:16:22Z","timestamp":1690661782000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/206\/6\/1365\/40621\/iNKT-cell-development-is-orchestrated-by-different"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,5,18]]},"references-count":35,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2009,6,8]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20090127","relation":{},"ISSN":["1540-9538","0022-1007"],"issn-type":[{"value":"1540-9538","type":"electronic"},{"value":"0022-1007","type":"print"}],"subject":[],"published":{"date-parts":[[2009,5,18]]}}}