{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T03:59:12Z","timestamp":1776916752763,"version":"3.51.2"},"reference-count":45,"publisher":"Elsevier BV","issue":"2","license":[{"start":{"date-parts":[[2021,4,1]],"date-time":"2021-04-01T00:00:00Z","timestamp":1617235200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2021,4,1]],"date-time":"2021-04-01T00:00:00Z","timestamp":1617235200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2021,3,19]],"date-time":"2021-03-19T00:00:00Z","timestamp":1616112000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["CEECIND\/03106\/2018"],"award-info":[{"award-number":["CEECIND\/03106\/2018"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["LISBOA-01-0145-FEDER-022170"],"award-info":[{"award-number":["LISBOA-01-0145-FEDER-022170"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PD\/BD\/114341\/2016"],"award-info":[{"award-number":["PD\/BD\/114341\/2016"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PD\/BD\/139190\/2018"],"award-info":[{"award-number":["PD\/BD\/139190\/2018"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PPBI-POCI-01-0145-FEDER-022122"],"award-info":[{"award-number":["PPBI-POCI-01-0145-FEDER-022122"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PTDC\/BIA-BID\/30925\/2017"],"award-info":[{"award-number":["PTDC\/BIA-BID\/30925\/2017"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005635","name":"Funda\u00e7\u00e3o Calouste Gulbenkian","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005635","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["cell.com","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Cell Reports"],"published-print":{"date-parts":[[2021,4]]},"DOI":"10.1016\/j.celrep.2021.108967","type":"journal-article","created":{"date-parts":[[2021,4,15]],"date-time":"2021-04-15T10:21:49Z","timestamp":1618482109000},"page":"108967","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":20,"title":["Self-renewal of double-negative 3 early thymocytes enables thymus autonomy but compromises the \u03b2-selection checkpoint"],"prefix":"10.1016","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0657-2283","authenticated-orcid":false,"given":"Rafael A.","family":"Paiva","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4779-6459","authenticated-orcid":false,"given":"Ant\u00f3nio G.G.","family":"Sousa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Camila V.","family":"Ramos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariana","family":"\u00c1vila","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1958-0231","authenticated-orcid":false,"given":"Jingtao","family":"Lilue","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tiago","family":"Paix\u00e3o","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8717-9709","authenticated-orcid":false,"given":"Vera C.","family":"Martins","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"78","reference":[{"key":"10.1016\/j.celrep.2021.108967_bib1","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.4049\/jimmunol.1801373","article-title":"T Cell Acute Lymphoblastic Leukemia as a Consequence of Thymus Autonomy","volume":"202","author":"Ballesteros-Arias","year":"2019","journal-title":"J.\u00a0Immunol."},{"key":"10.1016\/j.celrep.2021.108967_bib2","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1038\/nri3300","article-title":"Consortium biology in immunology: the perspective from the Immunological Genome Project","volume":"12","author":"Benoist","year":"2012","journal-title":"Nat. Rev. Immunol."},{"key":"10.1016\/j.celrep.2021.108967_bib3","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1084\/jem.20121412","article-title":"Self-renewal of thymocytes in the absence of competitive precursor replenishment","volume":"209","author":"Boehm","year":"2012","journal-title":"J.\u00a0Exp. Med."},{"key":"10.1016\/j.celrep.2021.108967_bib4","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/1074-7613(95)90047-0","article-title":"Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain","volume":"2","author":"Cao","year":"1995","journal-title":"Immunity"},{"key":"10.1016\/j.celrep.2021.108967_bib5","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1126\/science.288.5466.669","article-title":"Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease","volume":"288","author":"Cavazzana-Calvo","year":"2000","journal-title":"Science"},{"key":"10.1016\/j.celrep.2021.108967_bib6","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1038\/ni1234","article-title":"Notch promotes survival of pre-T cells at the beta-selection checkpoint by regulating cellular metabolism","volume":"6","author":"Ciofani","year":"2005","journal-title":"Nat. Immunol."},{"key":"10.1016\/j.celrep.2021.108967_bib7","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1084\/jem.175.4.1067","article-title":"Thymus-grafted SCID mice show transient thymopoiesis and limited depletion of V beta 11+ T\u00a0cells","volume":"175","author":"Frey","year":"1992","journal-title":"J.\u00a0Exp. Med."},{"key":"10.1016\/j.celrep.2021.108967_bib8","doi-asserted-by":"crossref","first-page":"2678","DOI":"10.1093\/bioinformatics\/bts503","article-title":"Qualimap: evaluating next-generation sequencing alignment data","volume":"28","author":"Garc\u00eda-Alcalde","year":"2012","journal-title":"Bioinformatics"},{"key":"10.1016\/j.celrep.2021.108967_bib9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.omtn.2016.11.011","article-title":"Limiting Thymic Precursor Supply Increases the Risk of Lymphoid Malignancy in Murine X-Linked Severe Combined Immunodeficiency","volume":"6","author":"Ginn","year":"2017","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"10.1016\/j.celrep.2021.108967_bib10","doi-asserted-by":"crossref","first-page":"2847","DOI":"10.1093\/bioinformatics\/btw313","article-title":"Complex heatmaps reveal patterns and correlations in multidimensional genomic data","volume":"32","author":"Gu","year":"2016","journal-title":"Bioinformatics"},{"key":"10.1016\/j.celrep.2021.108967_bib11","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1084\/jem.181.3.1187","article-title":"Development of CD4+CD8+ thymocytes in RAG-deficient mice through a T\u00a0cell receptor beta chain-independent pathway","volume":"181","author":"Guidos","year":"1995","journal-title":"J.\u00a0Exp. Med."},{"key":"10.1016\/j.celrep.2021.108967_bib12","doi-asserted-by":"crossref","first-page":"3132","DOI":"10.1172\/JCI35700","article-title":"Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1","volume":"118","author":"Hacein-Bey-Abina","year":"2008","journal-title":"J.\u00a0Clin. Invest."},{"key":"10.1016\/j.celrep.2021.108967_bib13","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1056\/NEJMoa1000164","article-title":"Efficacy of gene therapy for X-linked severe combined immunodeficiency","volume":"363","author":"Hacein-Bey-Abina","year":"2010","journal-title":"N.\u00a0Engl. J. Med."},{"key":"10.1016\/j.celrep.2021.108967_bib14","doi-asserted-by":"crossref","first-page":"858","DOI":"10.4049\/jimmunol.178.2.858","article-title":"Bone marrow-derived hemopoietic precursors commit to the T\u00a0cell lineage only after arrival in the thymic microenvironment","volume":"178","author":"Heinzel","year":"2007","journal-title":"J.\u00a0Immunol."},{"key":"10.1016\/j.celrep.2021.108967_bib15","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1002\/dvdy.24183","article-title":"Poly peak parser: Method and software for identification of unknown indels using sanger sequencing of polymerase chain reaction products","volume":"243","author":"Hill","year":"2014","journal-title":"Dev. Dyn."},{"key":"10.1016\/j.celrep.2021.108967_bib16","doi-asserted-by":"crossref","first-page":"3465","DOI":"10.4049\/jimmunol.1800774","article-title":"High-Throughput Single-Cell Sequencing of both TCR-\u03b2 Alleles","volume":"201","author":"Hosoya","year":"2018","journal-title":"J.\u00a0Immunol."},{"key":"10.1016\/j.celrep.2021.108967_bib17","doi-asserted-by":"crossref","first-page":"3143","DOI":"10.1172\/JCI35798","article-title":"Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients","volume":"118","author":"Howe","year":"2008","journal-title":"J.\u00a0Clin. Invest."},{"key":"10.1016\/j.celrep.2021.108967_bib18","doi-asserted-by":"crossref","first-page":"521","DOI":"10.2307\/3349979","article-title":"Cost sharing and the changing pattern of employer-sponsored health benefits","volume":"65","author":"Jensen","year":"1987","journal-title":"Milbank Q."},{"key":"10.1016\/j.celrep.2021.108967_bib19","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1084\/jem.183.4.1923","article-title":"p53 prevents maturation to the CD4+CD8+ stage of thymocyte differentiation in the absence of T\u00a0cell receptor rearrangement","volume":"183","author":"Jiang","year":"1996","journal-title":"J.\u00a0Exp. Med."},{"key":"10.1016\/j.celrep.2021.108967_bib20","doi-asserted-by":"crossref","first-page":"3441","DOI":"10.1038\/sj.emboj.7601761","article-title":"Notch-induced T\u00a0cell development requires phosphoinositide-dependent kinase 1","volume":"26","author":"Kelly","year":"2007","journal-title":"EMBO J."},{"key":"10.1016\/j.celrep.2021.108967_bib21","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nmeth.3317","article-title":"HISAT: a fast spliced aligner with low memory requirements","volume":"12","author":"Kim","year":"2015","journal-title":"Nat. Methods"},{"key":"10.1016\/j.celrep.2021.108967_bib22","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/nri3667","article-title":"Positive and negative selection of the T\u00a0cell repertoire: what thymocytes see (and don\u2019t see)","volume":"14","author":"Klein","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"10.1016\/j.celrep.2021.108967_bib23","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","article-title":"featureCounts: an efficient general purpose program for assigning sequence reads to genomic features","volume":"30","author":"Liao","year":"2014","journal-title":"Bioinformatics"},{"key":"10.1016\/j.celrep.2021.108967_bib24","doi-asserted-by":"crossref","first-page":"2531","DOI":"10.1182\/blood-2006-05-024190","article-title":"Coordination between CCR7- and CCR9-mediated chemokine signals in prevascular fetal thymus colonization","volume":"108","author":"Liu","year":"2006","journal-title":"Blood"},{"key":"10.1016\/j.celrep.2021.108967_bib25","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"10.1016\/j.celrep.2021.108967_bib26","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1038\/nprot.2016.138","article-title":"Separation and parallel sequencing of the genomes and transcriptomes of single cells using G&T-seq","volume":"11","author":"Macaulay","year":"2016","journal-title":"Nat. Protoc."},{"key":"10.1016\/j.celrep.2021.108967_bib27","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1084\/jem.20120846","article-title":"Thymus-autonomous T\u00a0cell development in the absence of progenitor import","volume":"209","author":"Martins","year":"2012","journal-title":"J.\u00a0Exp. Med."},{"key":"10.1016\/j.celrep.2021.108967_bib28","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/nature13317","article-title":"Cell competition is a tumour suppressor mechanism in the thymus","volume":"509","author":"Martins","year":"2014","journal-title":"Nature"},{"key":"10.1016\/j.celrep.2021.108967_bib29","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1038\/ni.2590","article-title":"The transcriptional landscape of \u03b1\u03b2 T\u00a0cell differentiation","volume":"14","author":"Mingueneau","year":"2013","journal-title":"Nat. Immunol."},{"key":"10.1016\/j.celrep.2021.108967_bib30","doi-asserted-by":"crossref","first-page":"4565","DOI":"10.1111\/febs.14651","article-title":"Thymus autonomy as a prelude to leukemia","volume":"285","author":"Paiva","year":"2018","journal-title":"FEBS J."},{"key":"10.1016\/j.celrep.2021.108967_bib31","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1084\/jem.20120845","article-title":"Thymocytes may persist and differentiate without any input from bone marrow progenitors","volume":"209","author":"Peaudecerf","year":"2012","journal-title":"J.\u00a0Exp. Med."},{"key":"10.1016\/j.celrep.2021.108967_bib32","doi-asserted-by":"crossref","first-page":"107910","DOI":"10.1016\/j.celrep.2020.107910","article-title":"Cell Competition, the Kinetics of Thymopoiesis, and Thymus Cellularity Are Regulated by Double-Negative 2 to 3 Early Thymocytes","volume":"32","author":"Ramos","year":"2020","journal-title":"Cell Rep."},{"key":"10.1016\/j.celrep.2021.108967_bib33","series-title":"R: A language and environment for statistical computing","year":"2020"},{"key":"10.1016\/j.celrep.2021.108967_bib34","doi-asserted-by":"crossref","first-page":"5678","DOI":"10.4049\/jimmunol.1502010","article-title":"Foxn1 Protein Expression in the Developing, Aging, and Regenerating Thymus","volume":"195","author":"Rode","year":"2015","journal-title":"J.\u00a0Immunol."},{"key":"10.1016\/j.celrep.2021.108967_bib35","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/nri2232","article-title":"Launching the T-cell-lineage developmental programme","volume":"8","author":"Rothenberg","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"10.1016\/j.celrep.2021.108967_bib36","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: an open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"10.1016\/j.celrep.2021.108967_bib37","doi-asserted-by":"crossref","first-page":"eaan0820","DOI":"10.1126\/scitranslmed.aan0820","article-title":"Preclinical modeling highlights the therapeutic potential of hematopoietic stem cell gene editing for correction of SCID-X1","volume":"9","author":"Schiroli","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"10.1016\/j.celrep.2021.108967_bib38","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":"10.1016\/j.celrep.2021.108967_bib39","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1016\/j.cell.2019.05.031","article-title":"Comprehensive Integration of Single-Cell Data","volume":"177","author":"Stuart","year":"2019","journal-title":"Cell"},{"key":"10.1016\/j.celrep.2021.108967_bib40","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.immuni.2005.11.012","article-title":"Developmental and molecular characterization of emerging beta- and gammadelta-selected pre-T cells in the adult mouse thymus","volume":"24","author":"Taghon","year":"2006","journal-title":"Immunity"},{"key":"10.1016\/j.celrep.2021.108967_bib41","doi-asserted-by":"crossref","first-page":"4199","DOI":"10.4049\/jimmunol.175.7.4199","article-title":"Regulated costimulation in the thymus is critical for T\u00a0cell development: dysregulated CD28 costimulation can bypass the pre-TCR checkpoint","volume":"175","author":"Williams","year":"2005","journal-title":"J.\u00a0Immunol."},{"key":"10.1016\/j.celrep.2021.108967_bib42","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1038\/nri3702","article-title":"Developmental gene networks: a triathlon on the course to T\u00a0cell identity","volume":"14","author":"Yui","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"10.1016\/j.celrep.2021.108967_bib43","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1084\/jem.20142143","article-title":"Multicongenic fate mapping quantification of dynamics of thymus colonization","volume":"212","author":"Zi\u0119tara","year":"2015","journal-title":"J.\u00a0Exp. Med."},{"key":"10.1016\/j.celrep.2021.108967_bib44","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1182\/blood-2009-08-237784","article-title":"CCR7 and CCR9 together recruit hematopoietic progenitors to the adult thymus","volume":"115","author":"Zlotoff","year":"2010","journal-title":"Blood"},{"key":"10.1016\/j.celrep.2021.108967_bib45","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1084\/jem.180.4.1517","article-title":"Sublethal gamma-radiation induces differentiation of CD4-\/CD8- into CD4+\/CD8+ thymocytes without T\u00a0cell receptor beta rearrangement in recombinase activation gene 2-\/- mice","volume":"180","author":"Z\u00fa\u00f1iga-Pfl\u00fccker","year":"1994","journal-title":"J.\u00a0Exp. Med."}],"container-title":["Cell Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S2211124721002813?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S2211124721002813?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T11:19:33Z","timestamp":1761909573000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S2211124721002813"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4]]},"references-count":45,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2021,4]]}},"alternative-id":["S2211124721002813"],"URL":"https:\/\/doi.org\/10.1016\/j.celrep.2021.108967","relation":{},"ISSN":["2211-1247"],"issn-type":[{"value":"2211-1247","type":"print"}],"subject":[],"published":{"date-parts":[[2021,4]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Self-renewal of double-negative 3 early thymocytes enables thymus autonomy but compromises the \u03b2-selection checkpoint","name":"articletitle","label":"Article Title"},{"value":"Cell Reports","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.celrep.2021.108967","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2021 The Authors.","name":"copyright","label":"Copyright"}],"article-number":"108967"}}