{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T04:57:25Z","timestamp":1776920245183,"version":"3.51.2"},"reference-count":64,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2018,6,28]],"date-time":"2018-06-28T00:00:00Z","timestamp":1530144000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["MOP\u2010119538"],"award-info":[{"award-number":["MOP\u2010119538"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["MOP\u201042387"],"award-info":[{"award-number":["MOP\u201042387"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["FND\u2010154332"],"award-info":[{"award-number":["FND\u2010154332"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1P01AI102853\u201001"],"award-info":[{"award-number":["1P01AI102853\u201001"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004089","name":"Krembil Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004089","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Immunol Cell Biol"],"published-print":{"date-parts":[[2018,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>\u03b3\u03b4 T\u2010cells perform a wide range of tissue\u2010 and disease\u2010specific functions that are dependent on the effector cytokines produced by these cells. However, the aggregate signals required for the development of interferon\u2010\u03b3 (<jats:styled-content style=\"fixed-case\">IFN<\/jats:styled-content>\u03b3) and interleukin\u201017 (<jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u201017) producing \u03b3\u03b4 T\u2010cells remain unknown. Here, we define the cues involved in the functional programming of \u03b3\u03b4 T\u2010cells, by examining the roles of T\u2010cell receptor (<jats:styled-content style=\"fixed-case\">TCR<\/jats:styled-content>), Notch, and cytokine\u2010receptor signaling. <jats:styled-content style=\"fixed-case\">KN<\/jats:styled-content>6 \u03b3\u03b4<jats:styled-content style=\"fixed-case\">TCR<\/jats:styled-content>\u2010transduced <jats:italic>Rag2<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> T\u2010cell progenitors were cultured on stromal cells variably expressing <jats:styled-content style=\"fixed-case\">TCR<\/jats:styled-content> and Notch ligands, supplemented with different cytokines. We found that distinct combinations of these signals are required to program <jats:styled-content style=\"fixed-case\">IFN<\/jats:styled-content>\u03b3 <jats:italic>versus <\/jats:italic><jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u201017 producing \u03b3\u03b4 T\u2010cell subsets, with Notch and weak <jats:styled-content style=\"fixed-case\">TCR<\/jats:styled-content> ligands optimally enabling development of \u03b3\u03b417 cells in the presence of <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20101\u03b2, <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u201021 and <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u201023. Notably, these cytokines were also shown to be required for the intrathymic development of \u03b3\u03b417 cells. Together, this work provides a framework of how signals downstream of <jats:styled-content style=\"fixed-case\">TCR<\/jats:styled-content>, Notch and cytokine receptors integrate to program the effector function of <jats:styled-content style=\"fixed-case\">IFN<\/jats:styled-content>\u03b3 and <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u201017 producing \u03b3\u03b4 T\u2010cell subsets.<\/jats:p>","DOI":"10.1111\/imcb.12164","type":"journal-article","created":{"date-parts":[[2018,5,13]],"date-time":"2018-05-13T08:41:40Z","timestamp":1526200900000},"page":"994-1007","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Integration of T\u2010cell receptor, Notch and cytokine signals programs mouse \u03b3\u03b4 T\u2010cell effector differentiation"],"prefix":"10.1111","volume":"96","author":[{"given":"Payam","family":"Zarin","sequence":"first","affiliation":[{"name":"Department of Immunology University of Toronto, and Sunnybrook Research Institute 2075 Bayview Ave. Toronto ON M4N 3M5 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tracy SH","family":"In","sequence":"additional","affiliation":[{"name":"Department of Immunology University of Toronto, and Sunnybrook Research Institute 2075 Bayview Ave. Toronto ON M4N 3M5 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward LY","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Immunology University of Toronto, and Sunnybrook Research Institute 2075 Bayview Ave. Toronto ON M4N 3M5 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jastaranpreet","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Immunology University of Toronto, and Sunnybrook Research Institute 2075 Bayview Ave. Toronto ON M4N 3M5 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gladys W","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Immunology University of Toronto, and Sunnybrook Research Institute 2075 Bayview Ave. Toronto ON M4N 3M5 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mahmood","family":"Mohtashami","sequence":"additional","affiliation":[{"name":"Department of Immunology University of Toronto, and Sunnybrook Research Institute 2075 Bayview Ave. Toronto ON M4N 3M5 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David L","family":"Wiest","sequence":"additional","affiliation":[{"name":"Blood Cell Development and Cancer Keystone Immune Cell Development and Host Defense Program Fox Chase Cancer Center 333 Cottman Avenue Philadelphia PA 19111\u20102497 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michele K","family":"Anderson","sequence":"additional","affiliation":[{"name":"Department of Immunology University of Toronto, and Sunnybrook Research Institute 2075 Bayview Ave. Toronto ON M4N 3M5 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2538-3178","authenticated-orcid":false,"given":"Juan Carlos","family":"Z\u00fa\u00f1iga\u2010Pfl\u00fccker","sequence":"additional","affiliation":[{"name":"Department of Immunology University of Toronto, and Sunnybrook Research Institute 2075 Bayview Ave. Toronto ON M4N 3M5 Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2018,6,28]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri2781"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-14-3228"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1508990112"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2015.09.014"},{"key":"e_1_2_7_6_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fimmu.2016.00014","article-title":"The emerging roles of gamma\u2010delta T cells in tissue inflammation in experimental autoimmune encephalomyelitis","volume":"7","author":"Malik S","year":"2016","journal-title":"Front Immunol"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature14282"},{"key":"e_1_2_7_8_1","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1126\/scitranslmed.aad8996","article-title":"Chronic skin inflammation leads to bone loss by IL\u201017\u2010mediated inhibition of Wnt signaling in osteoblasts","volume":"8","author":"Uluckan O","year":"2016","journal-title":"Sci Transl Med"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellimm.2015.03.007"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2008.04.022"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1010890108"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2773"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3424"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2012.11.004"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2009.07.010"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.05.071"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1601301"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20080034"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2009.08.001"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature05969"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.05.088"},{"key":"e_1_2_7_22_1","doi-asserted-by":"crossref","first-page":"39117","DOI":"10.1038\/srep39117","article-title":"Notch regulates Th17 differentiation and controls trafficking of IL\u201017 and metabolic regulators within Th17 cells in a context\u2010dependent manner","volume":"6","author":"Coutaz M","year":"2016","journal-title":"Sci Rep"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0804322"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-02-334995"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1401619"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/342931a0"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.5650050716"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90170-8"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1106885"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20041257"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1312872111"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1717"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-01-331298"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20060285"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4986"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1003597"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-08-520445"},{"key":"e_1_2_7_38_1","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/978-1-4614-6217-0_11","article-title":"Differentiation and activation of gammadelta T Lymphocytes: focus on CD27 and CD28 costimulatory receptors","volume":"785","author":"Ribot JC","year":"2013","journal-title":"Adv Exp Med Biol"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0911755107"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0089266"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2016.00132"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4753"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2009.09.024"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni1008-1091"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.09.036"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1500375"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200939922"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830120710"},{"key":"e_1_2_7_49_1","first-page":"pdb\u2010prot4808","article-title":"Fetal thymus organ culture","volume":"2007","author":"Anderson G","year":"2007","journal-title":"CSH Protoc"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201343759"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1718328115"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-02225-5"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.04.018"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2006.05.010"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.3109\/08830185.2013.783831"},{"key":"e_1_2_7_56_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201242569"},{"key":"e_1_2_7_57_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0903539"},{"key":"e_1_2_7_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(92)90029-C"},{"key":"e_1_2_7_59_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.9.5230"},{"key":"e_1_2_7_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(02)00474-0"},{"key":"e_1_2_7_61_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1000782"},{"key":"e_1_2_7_62_1","first-page":"219","article-title":"Assays of thymic selection. Fetal thymus organ culture and in\u00a0vitro thymocyte dulling assay","volume":"156","author":"Hogquist KA","year":"2001","journal-title":"Methods Mol Biol"},{"key":"e_1_2_7_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2005.04.003"},{"key":"e_1_2_7_64_1","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxt027"},{"key":"e_1_2_7_65_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20131540"}],"container-title":["Immunology &amp; Cell Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fimcb.12164","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/imcb.12164","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,16]],"date-time":"2023-09-16T13:27:14Z","timestamp":1694870834000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/imcb.12164"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,6,28]]},"references-count":64,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2018,10]]}},"alternative-id":["10.1111\/imcb.12164"],"URL":"https:\/\/doi.org\/10.1111\/imcb.12164","archive":["Portico"],"relation":{},"ISSN":["0818-9641","1440-1711"],"issn-type":[{"value":"0818-9641","type":"print"},{"value":"1440-1711","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,6,28]]},"assertion":[{"value":"2018-01-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-05-06","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-06-28","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}