{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T13:08:07Z","timestamp":1791119287465,"version":"4.1.0"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2014,3,1]],"date-time":"2014-03-01T00:00:00Z","timestamp":1393632000000},"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":[[2014,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Cytotoxicity and IFN-\u03b3 production by human \u03b3\u03b4 T cells underlie their potent antitumor functions. However, it remains unclear where and how human \u03b3\u03b4 T cells acquire these key effector properties. Given the recent disclosure of a major contribution of the thymus to murine \u03b3\u03b4 T cell functional differentiation, in this study we have analyzed a series of human pediatric thymuses. We found that ex vivo\u2013isolated \u03b3\u03b4 thymocytes produced negligible IFN-\u03b3 and lacked cytolytic activity against leukemia cells. However, these properties were selectively acquired upon stimulation with IL-2 or IL-15, but not IL-4 or IL-7. Unexpectedly, TCR activation was dispensable for these stages of functional differentiation. The effects of IL-2\/IL-15 depended on MAPK\/ERK signaling and induced de novo expression of the transcription factors T-bet and eomesodermin, as well as the cytolytic enzyme perforin, required for the cytotoxic type 1 program. These findings have implications for the manipulation of \u03b3\u03b4 T cells in cancer immunotherapy.<\/jats:p>","DOI":"10.4049\/jimmunol.1303119","type":"journal-article","created":{"date-parts":[[2014,2,1]],"date-time":"2014-02-01T02:39:30Z","timestamp":1391222370000},"page":"2237-2243","source":"Crossref","is-referenced-by-count":125,"title":["Human \u03b3\u03b4 Thymocytes Are Functionally Immature and Differentiate into Cytotoxic Type 1 Effector T Cells upon IL-2\/IL-15 Signaling"],"prefix":"10.1093","volume":"192","author":[{"given":"Julie C","family":"Ribot","sequence":"first","affiliation":[{"name":"Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa , 1649-028 Lisbon,","place":["Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9rgio T","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa , 1649-028 Lisbon,","place":["Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel V","family":"Correia","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa , 1649-028 Lisbon,","place":["Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana E","family":"Sousa","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa , 1649-028 Lisbon,","place":["Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Silva-Santos","sequence":"additional","affiliation":[{"name":"Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa , 1649-028 Lisbon,","place":["Portugal"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,3,1]]},"reference":[{"key":"2025032404172999900_r1","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/nature12467","article-title":"Evolutionary implications of a third lymphocyte lineage in lampreys","volume":"501","author":"Hirano","year":"2013","journal-title":"Nature"},{"key":"2025032404172999900_r2","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.immuni.2009.08.006","article-title":"\u03b3\u03b4 T cells and the lymphoid stress-surveillance response","volume":"31","author":"Hayday","year":"2009","journal-title":"Immunity"},{"key":"2025032404172999900_r3","doi-asserted-by":"crossref","first-page":"10024","DOI":"10.1158\/0008-5472.CAN-10-3236","article-title":"Targeting \u03b3\u03b4 T lymphocytes for cancer immunotherapy: from novel mechanistic insight to clinical application","volume":"70","author":"Gomes","year":"2010","journal-title":"Cancer Res."},{"key":"2025032404172999900_r4","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.it.2012.01.006","article-title":"Harnessing \u03b3\u03b4 T cells in anticancer immunotherapy","volume":"33","author":"Hannani","year":"2012","journal-title":"Trends Immunol."},{"key":"2025032404172999900_r5","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1084\/jem.20031981","article-title":"Innate immune surveillance of spontaneous B cell lymphomas by natural killer cells and \u03b3\u03b4 T cells","volume":"199","author":"Street","year":"2004","journal-title":"J. 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