{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T14:30:30Z","timestamp":1790778630223,"version":"4.1.0"},"reference-count":79,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2022,1,1]],"date-time":"2022-01-01T00:00:00Z","timestamp":1640995200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100009425","name":"Landsteiner Foundation for Blood Transfusion Research","doi-asserted-by":"publisher","award":["1826"],"award-info":[{"award-number":["1826"]}],"id":[{"id":"10.13039\/100009425","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009425","name":"Landsteiner Foundation for Blood Transfusion Research","doi-asserted-by":"publisher","award":["1430"],"award-info":[{"award-number":["1430"]}],"id":[{"id":"10.13039\/100009425","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,1,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>CD4+CD25+FOXP3+ regulatory T (Treg) cells control immunological tolerance. Treg cells are generated in the thymus (tTreg) or in the periphery. Their superior lineage fidelity makes tTregs the preferred cell type for adoptive cell therapy (ACT). How human tTreg cells develop is incompletely understood. By combining single-cell transcriptomics and flow cytometry, we in this study delineated three major Treg developmental stages in the human thymus. At the first stage, which we propose to name pre-Treg I, cells still express lineage-inappropriate genes and exhibit signs of TCR signaling, presumably reflecting recognition of self-antigen. The subsequent pre-Treg II stage is marked by the sharp appearance of transcription factor FOXO1 and features induction of KLF2 and CCR7, in apparent preparation for thymic exit. The pre-Treg II stage can further be refined based on the sequential acquisition of surface markers CD31 and GPA33. The expression of CD45RA, finally, completes the phenotype also found on mature recent thymic emigrant Treg cells. Remarkably, the thymus contains a substantial fraction of recirculating mature effector Treg cells, distinguishable by expression of inflammatory chemokine receptors and absence of CCR7. The developmental origin of these cells is unclear and warrants caution when using thymic tissue as a source of stable cells for ACT. We show that cells in the major developmental stages can be distinguished using the surface markers CD1a, CD27, CCR7, and CD39, allowing for their viable isolation. These insights help identify fully mature tTreg cells for ACT and can serve as a basis for further mechanistic studies into tTreg development.<\/jats:p>","DOI":"10.4049\/jimmunol.2100506","type":"journal-article","created":{"date-parts":[[2021,12,22]],"date-time":"2021-12-22T16:35:34Z","timestamp":1640190934000},"page":"384-395","source":"Crossref","is-referenced-by-count":26,"title":["Single-Cell Transcriptomics Reveals Discrete Steps in Regulatory T Cell Development in the Human Thymus"],"prefix":"10.1093","volume":"208","author":[{"given":"Florencia","family":"Morgana","sequence":"first","affiliation":[{"name":"Department of Hematopoiesis, Sanquin Research , Amsterdam,","place":["the Netherlands"]},{"name":"Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rianne","family":"Opstelten","sequence":"additional","affiliation":[{"name":"Department of Hematopoiesis, Sanquin Research , Amsterdam,","place":["the Netherlands"]},{"name":"Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manon C","family":"Slot","sequence":"additional","affiliation":[{"name":"Department of Hematopoiesis, Sanquin Research , Amsterdam,","place":["the Netherlands"]},{"name":"Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew M","family":"Scott","sequence":"additional","affiliation":[{"name":"Tumor Targeting Laboratory, Olivia Newton-John Cancer Research Institute , Melbourne,","place":["Australia"]},{"name":"School of Cancer Medicine, La Trobe University , Melbourne,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9 A W","family":"van Lier","sequence":"additional","affiliation":[{"name":"Department of Hematopoiesis, Sanquin Research , Amsterdam,","place":["the Netherlands"]},{"name":"Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca","family":"Blom","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam , Amsterdam,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8601-2149","authenticated-orcid":false,"given":"Ahmed","family":"Mahfouz","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center , Leiden,","place":["the Netherlands"]},{"name":"Delft Bioinformatics Lab, Delft University of Technology , Delft,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derk","family":"Amsen","sequence":"additional","affiliation":[{"name":"Department of Hematopoiesis, Sanquin Research , Amsterdam,","place":["the Netherlands"]},{"name":"Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam ,","place":["the Netherlands"]},{"name":"Amsterdam Institute for Infection and Immunity, University of Amsterdam , Amsterdam,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,1,15]]},"reference":[{"key":"2025021008493349300_r1","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/ni1178","article-title":"Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self","volume":"6","author":"Sakaguchi","year":"2005","journal-title":"Nat. Immunol."},{"key":"2025021008493349300_r2","doi-asserted-by":"crossref","first-page":"1710","DOI":"10.1016\/j.jaci.2018.10.015","article-title":"Regulatory T-cell therapy for autoimmune and autoinflammatory diseases: The next frontier","volume":"142","author":"Esensten","year":"2018","journal-title":"J. Allergy Clin. Immunol."},{"key":"2025021008493349300_r3","doi-asserted-by":"crossref","first-page":"304ps18","DOI":"10.1126\/scitranslmed.aaa7721","article-title":"Hurdles in therapy with regulatory T cells","volume":"7","author":"Trzonkowski","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"2025021008493349300_r4","doi-asserted-by":"crossref","first-page":"2030","DOI":"10.4049\/jimmunol.1500703","article-title":"Phenotypic complexity of the human regulatory T cell compartment revealed by mass cytometry","volume":"195","author":"Mason","year":"2015","journal-title":"J. Immunol."},{"key":"2025021008493349300_r5","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1038\/nature07674","article-title":"Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses","volume":"458","author":"Zheng","year":"2009","journal-title":"Nature"},{"key":"2025021008493349300_r6","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1038\/ni.1731","article-title":"The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation","volume":"10","author":"Koch","year":"2009","journal-title":"Nat. Immunol."},{"key":"2025021008493349300_r7","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.immuni.2019.01.001","article-title":"Single-cell transcriptomics of regulatory T cells reveals trajectories of tissue adaptation","volume":"50","author":"Miragaia","year":"2019","journal-title":"Immunity"},{"key":"2025021008493349300_r8","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1084\/jem.20120914","article-title":"Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells","volume":"209","author":"Weiss","year":"2012","journal-title":"J. Exp. Med."},{"key":"2025021008493349300_r9","doi-asserted-by":"crossref","first-page":"3433","DOI":"10.4049\/jimmunol.0904028","article-title":"Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells","volume":"184","author":"Thornton","year":"2010","journal-title":"J. Immunol."},{"key":"2025021008493349300_r10","doi-asserted-by":"crossref","first-page":"3180","DOI":"10.4049\/jimmunol.1203473","article-title":"Active demethylation of the Foxp3 locus leads to the generation of stable regulatory T cells within the thymus","volume":"190","author":"Toker","year":"2013","journal-title":"J. Immunol."},{"key":"2025021008493349300_r11","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1016\/j.it.2016.08.012","article-title":"Induced regulatory T cells: their development, stability, and applications","volume":"37","author":"Kanamori","year":"2016","journal-title":"Trends Immunol."},{"key":"2025021008493349300_r12","doi-asserted-by":"crossref","first-page":"3091","DOI":"10.1002\/eji.200939432","article-title":"Alloantigen-specific de novo-induced Foxp3+ Treg revert in vivo and do not protect from experimental GVHD","volume":"39","author":"Koenecke","year":"2009","journal-title":"Eur. J. Immunol."},{"key":"2025021008493349300_r13","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1002\/eji.200839040","article-title":"Neuropilin-1 is not a marker of human Foxp3+ Treg","volume":"39","author":"Milpied","year":"2009","journal-title":"Eur. J. Immunol."},{"key":"2025021008493349300_r14","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1002\/eji.201847935","article-title":"Helios+ and Helios- Treg subpopulations are phenotypically and functionally distinct and express dissimilar TCR repertoires","volume":"49","author":"Thornton","year":"2019","journal-title":"Eur. J. Immunol."},{"key":"2025021008493349300_r15","doi-asserted-by":"crossref","first-page":"e24226","DOI":"10.1371\/journal.pone.0024226","article-title":"Helios expression is a marker of T cell activation and proliferation","volume":"6","author":"Akimova","year":"2011","journal-title":"PLoS One"},{"key":"2025021008493349300_r16","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1111\/ajt.13456","article-title":"Discarded human thymus is a novel source of stable and long-lived therapeutic regulatory T cells","volume":"16","author":"Dijke","year":"2016","journal-title":"Am. J. Transplant."},{"key":"2025021008493349300_r17","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.immuni.2007.11.021","article-title":"A two-step process for thymic regulatory T cell development","volume":"28","author":"Lio","year":"2008","journal-title":"Immunity"},{"key":"2025021008493349300_r18","doi-asserted-by":"crossref","first-page":"2261","DOI":"10.4049\/jimmunol.0901304","article-title":"Rare development of Foxp3+ thymocytes in the CD4+CD8+ subset","volume":"183","author":"Lee","year":"2009","journal-title":"J. Immunol."},{"key":"2025021008493349300_r19","doi-asserted-by":"crossref","first-page":"3604","DOI":"10.1002\/eji.201141614","article-title":"Differentiation of human thymic regulatory T cells at the double positive stage","volume":"41","author":"Nunes-Caba\u00e7o","year":"2011","journal-title":"Eur. J. Immunol."},{"key":"2025021008493349300_r20","doi-asserted-by":"crossref","first-page":"4715","DOI":"10.1182\/blood-2004-10-4051","article-title":"Ontogeny of CD4+CD25+ regulatory\/suppressor T cells in human fetuses","volume":"105","author":"Darrasse-J\u00e8ze","year":"2005","journal-title":"Blood"},{"key":"2025021008493349300_r21","doi-asserted-by":"crossref","first-page":"2031","DOI":"10.4049\/jimmunol.1900662","article-title":"Regulatory T cell development in the thymus","volume":"203","author":"Owen","year":"2019","journal-title":"J. Immunol."},{"key":"2025021008493349300_r22","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/ni.2849","article-title":"Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells","volume":"15","author":"Mahmud","year":"2014","journal-title":"Nat. Immunol."},{"key":"2025021008493349300_r23","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1084\/jem.20112061","article-title":"Epithelial and dendritic cells in the thymic medulla promote CD4+Foxp3+ regulatory T cell development via the CD27-CD70 pathway","volume":"210","author":"Coquet","year":"2013","journal-title":"J. Exp. Med."},{"key":"2025021008493349300_r24","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.immuni.2007.11.022","article-title":"Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire","volume":"28","author":"Burchill","year":"2008","journal-title":"Immunity"},{"key":"2025021008493349300_r25","doi-asserted-by":"crossref","first-page":"5368","DOI":"10.1038\/s41467-018-07806-6","article-title":"Interleukin 2 modulates thymic-derived regulatory T cell epigenetic landscape","volume":"9","author":"Chorro","year":"2018","journal-title":"Nat. Commun."},{"key":"2025021008493349300_r26","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.cels.2016.09.002","article-title":"A single-cell transcriptome atlas of the human pancreas","volume":"3","author":"Muraro","year":"2016","journal-title":"Cell Syst."},{"key":"2025021008493349300_r27","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1038\/nbt.3192","article-title":"Spatial reconstruction of single-cell gene expression data","volume":"33","author":"Satija","year":"2015","journal-title":"Nat. Biotechnol."},{"key":"2025021008493349300_r28","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s13059-016-0888-1","article-title":"Classification of low quality cells from single-cell RNA-seq data","volume":"17","author":"Ilicic","year":"2016","journal-title":"Genome Biol."},{"key":"2025021008493349300_r29","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1186\/s12864-018-4772-0","article-title":"Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics","volume":"19","author":"Street","year":"2018","journal-title":"BMC Genomics"},{"key":"2025021008493349300_r30","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1189\/jlb.1A0415-164R","article-title":"Interleukin-7 promotes human regulatory T cell development at the CD4+CD8+ double-positive thymocyte stage","volume":"100","author":"Tuulasvaara","year":"2016","journal-title":"J. Leukoc. Biol."},{"key":"2025021008493349300_r31","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1038\/s41590-018-0289-6","article-title":"Thymic regulatory T cells arise via two distinct developmental programs","volume":"20","author":"Owen","year":"2019","journal-title":"Nat. Immunol."},{"key":"2025021008493349300_r32","doi-asserted-by":"crossref","first-page":"3651","DOI":"10.4049\/jimmunol.180.6.3651","article-title":"Cutting edge: human CD4-CD8- thymocytes express FOXP3 in the absence of a TCR","volume":"180","author":"Tuovinen","year":"2008","journal-title":"J. Immunol."},{"key":"2025021008493349300_r33","doi-asserted-by":"crossref","first-page":"eaay3224","DOI":"10.1126\/science.aay3224","article-title":"A cell atlas of human thymic development defines T cell repertoire formation","volume":"367","author":"Park","year":"2020","journal-title":"Science"},{"key":"2025021008493349300_r34","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1084\/jem.20080996","article-title":"Human CD4+ T cell recent thymic emigrants are identified by protein tyrosine kinase 7 and have reduced immune function","volume":"206","author":"Haines","year":"2009","journal-title":"J. Exp. Med."},{"key":"2025021008493349300_r35","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.immuni.2008.12.022","article-title":"Regulatory T cells sequentially migrate from inflamed tissues to draining lymph nodes to suppress the alloimmune response","volume":"30","author":"Zhang","year":"2009","journal-title":"Immunity"},{"key":"2025021008493349300_r36","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1084\/jem.20031562","article-title":"Developmental stage, phenotype, and migration distinguish naive- and effector\/memory-like CD4+ regulatory T cells","volume":"199","author":"Huehn","year":"2004","journal-title":"J. Exp. Med."},{"key":"2025021008493349300_r37","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1038\/44385","article-title":"Two subsets of memory T lymphocytes with distinct homing potentials and effector functions","volume":"401","author":"Sallusto","year":"1999","journal-title":"Nature"},{"key":"2025021008493349300_r38","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1016\/j.immuni.2008.03.018","article-title":"Two functional subsets of FOXP3+ regulatory T cells in human thymus and periphery","volume":"28","author":"Ito","year":"2008","journal-title":"Immunity"},{"key":"2025021008493349300_r39","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1038\/ni.3150","article-title":"Peripheral regulatory T lymphocytes recirculating to the thymus suppress the development of their precursors","volume":"16","author":"Thiault","year":"2015","journal-title":"Nat. Immunol."},{"key":"2025021008493349300_r40","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/s41423-019-0352-8","article-title":"Recirculating IL-1R2+ Tregs fine-tune intrathymic Treg development under inflammatory conditions","volume":"18","author":"Nikolouli","year":"2021","journal-title":"Cell. Mol. Immunol."},{"key":"2025021008493349300_r41","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1002\/eji.201444787","article-title":"BST2\/Tetherin is constitutively expressed on human thymocytes with the phenotype and function of Treg cells","volume":"45","author":"Epeldegui","year":"2015","journal-title":"Eur. J. Immunol."},{"key":"2025021008493349300_r42","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/1074-7613(95)90113-2","article-title":"A role for the orphan steroid receptor Nur77 in apoptosis accompanying antigen-induced negative selection","volume":"3","author":"Calnan","year":"1995","journal-title":"Immunity"},{"key":"2025021008493349300_r43","doi-asserted-by":"crossref","first-page":"3891","DOI":"10.1073\/pnas.1200090109","article-title":"Nuclear receptor Nr4a1 modulates both regulatory T-cell (Treg) differentiation and clonal deletion","volume":"109","author":"Fassett","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025021008493349300_r44","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1084\/jem.20110308","article-title":"T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse","volume":"208","author":"Moran","year":"2011","journal-title":"J. Exp. Med."},{"key":"2025021008493349300_r45","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1084\/jem.190.2.217","article-title":"ITM2A is induced during thymocyte selection and T cell activation and causes downregulation of CD8 when overexpressed in CD4(+)CD8(+) double positive thymocytes","volume":"190","author":"Kirchner","year":"1999","journal-title":"J. Exp. Med."},{"key":"2025021008493349300_r46","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/ni.3646","article-title":"Guidance of regulatory T cell development by Satb1-dependent super-enhancer establishment. [Published errata appear in 2017 Nat. Immunol. 18: 474 and 2017 Nat. Immunol. 18: 1270.]","volume":"18","author":"Kitagawa","year":"2017","journal-title":"Nat. Immunol."},{"key":"2025021008493349300_r47","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1038\/nature04882","article-title":"Kruppel-like factor 2 regulates thymocyte and T-cell migration","volume":"442","author":"Carlson","year":"2006","journal-title":"Nature"},{"key":"2025021008493349300_r48","doi-asserted-by":"crossref","first-page":"7632","DOI":"10.4049\/jimmunol.178.12.7632","article-title":"Kruppel-like factor 2 controls T cell trafficking by activating L-selectin (CD62L) and sphingosine-1-phosphate receptor 1 transcription","volume":"178","author":"Bai","year":"2007","journal-title":"J. Immunol."},{"key":"2025021008493349300_r49","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1016\/j.immuni.2010.12.002","article-title":"Foxo transcription factors control regulatory T cell development and function. [Published erratum appears in 2011 Immunity 34: 135.]","volume":"33","author":"Kerdiles","year":"2010","journal-title":"Immunity"},{"key":"2025021008493349300_r50","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1038\/ni.1884","article-title":"Foxo proteins cooperatively control the differentiation of Foxp3+ regulatory T cells","volume":"11","author":"Ouyang","year":"2010","journal-title":"Nat. Immunol."},{"key":"2025021008493349300_r51","doi-asserted-by":"crossref","first-page":"5415","DOI":"10.1038\/s41467-019-13055-y","article-title":"Automated optimized parameters for T-distributed stochastic neighbor embedding improve visualization and analysis of large datasets","volume":"10","author":"Belkina","year":"2019","journal-title":"Nat. Commun."},{"key":"2025021008493349300_r52","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1002\/eji.200425763","article-title":"Development and activation of regulatory T cells in the human fetus","volume":"35","author":"Cupedo","year":"2005","journal-title":"Eur. J. Immunol."},{"key":"2025021008493349300_r53","doi-asserted-by":"crossref","first-page":"3139","DOI":"10.4049\/jimmunol.1901250","article-title":"GPA33: a marker to identify stable human regulatory T cells","volume":"204","author":"Opstelten","year":"2020","journal-title":"J. Immunol."},{"key":"2025021008493349300_r54","doi-asserted-by":"crossref","first-page":"4053","DOI":"10.1172\/JCI81187","article-title":"TIGIT predominantly regulates the immune response via regulatory T cells","volume":"125","author":"Kurtulus","year":"2015","journal-title":"J. Clin. Invest."},{"key":"2025021008493349300_r55","doi-asserted-by":"crossref","first-page":"145","DOI":"10.4049\/jimmunol.1402381","article-title":"Divergent phenotypes of human regulatory T cells expressing the receptors TIGIT and CD226","volume":"195","author":"Fuhrman","year":"2015","journal-title":"J. Immunol."},{"key":"2025021008493349300_r56","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.immuni.2014.02.012","article-title":"Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses","volume":"40","author":"Joller","year":"2014","journal-title":"Immunity"},{"key":"2025021008493349300_r57","doi-asserted-by":"crossref","first-page":"2310","DOI":"10.4049\/jimmunol.1500350","article-title":"CD31, a valuable marker to identify early and late stages of T cell differentiation in the human thymus","volume":"198","author":"Douaisi","year":"2017","journal-title":"J. Immunol."},{"key":"2025021008493349300_r58","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1084\/jem.20040643","article-title":"CCR7 signals are essential for cortex-medulla migration of developing thymocytes","volume":"200","author":"Ueno","year":"2004","journal-title":"J. Exp. Med."},{"key":"2025021008493349300_r59","doi-asserted-by":"crossref","first-page":"3999","DOI":"10.4049\/jimmunol.172.7.3999","article-title":"CCR7 directs the migration of thymocytes into the thymic medulla","volume":"172","author":"Kwan","year":"2004","journal-title":"J. Immunol."},{"key":"2025021008493349300_r60","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/S1074-7613(02)00267-4","article-title":"Role for CCR7 ligands in the emigration of newly generated T lymphocytes from the neonatal thymus","volume":"16","author":"Ueno","year":"2002","journal-title":"Immunity"},{"key":"2025021008493349300_r61","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1016\/j.immuni.2009.03.019","article-title":"Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor","volume":"30","author":"Miyara","year":"2009","journal-title":"Immunity"},{"key":"2025021008493349300_r62","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1016\/j.immuni.2018.04.008","article-title":"Proteomic analyses of human regulatory T cells reveal adaptations in signaling pathways that protect cellular identity","volume":"48","author":"Cuadrado","year":"2018","journal-title":"Immunity"},{"key":"2025021008493349300_r63","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1002\/eji.201747375","article-title":"Aire controls the recirculation of murine Foxp3+ regulatory T-cells back to the thymus","volume":"48","author":"Cowan","year":"2018","journal-title":"Eur. J. Immunol."},{"key":"2025021008493349300_r64","doi-asserted-by":"crossref","first-page":"2712","DOI":"10.1002\/eji.201444529","article-title":"Both retention and recirculation contribute to long-lived regulatory T-cell accumulation in the thymus","volume":"44","author":"Yang","year":"2014","journal-title":"Eur. J. Immunol."},{"key":"2025021008493349300_r65","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1093\/intimm\/dxm010","article-title":"The origin of thymic CD4+CD25+ regulatory T cells and their co-stimulatory requirements are determined after elimination of recirculating peripheral CD4+ cells","volume":"19","author":"Zhan","year":"2007","journal-title":"Int. Immunol."},{"key":"2025021008493349300_r66","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1038\/ni.2683","article-title":"Regulatory T cells in nonlymphoid tissues","volume":"14","author":"Burzyn","year":"2013","journal-title":"Nat. Immunol."},{"key":"2025021008493349300_r67","first-page":"4503","volume":"121","author":"Wohlfert","year":"2011","journal-title":"GATA3 controls Foxp3+ regulatory T cell fate during inflammation in mice"},{"key":"2025021008493349300_r68","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1038\/nm.2002","article-title":"Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters","volume":"15","author":"Feuerer","year":"2009","journal-title":"Nat. Med."},{"key":"2025021008493349300_r69","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1016\/j.cell.2013.10.054","article-title":"A special population of regulatory T cells potentiates muscle repair","volume":"155","author":"Burzyn","year":"2013","journal-title":"Cell"},{"key":"2025021008493349300_r70","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/ni.3085","article-title":"The transcriptional regulators IRF4, BATF and IL-33 orchestrate development and maintenance of adipose tissue-resident regulatory T cells. [Published erratum appears in 2015 Nat. Immunol. 16: 544.]","volume":"16","author":"Vasanthakumar","year":"2015","journal-title":"Nat. Immunol."},{"key":"2025021008493349300_r71","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1038\/s41590-019-0316-2","article-title":"c-Maf-dependent Treg cell control of intestinal TH17 cells and IgA establishes host-microbiota homeostasis","volume":"20","author":"Neumann","year":"2019","journal-title":"Nat. Immunol."},{"key":"2025021008493349300_r72","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1038\/ni.2006","article-title":"The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells","volume":"12","author":"Cretney","year":"2011","journal-title":"Nat. Immunol."},{"key":"2025021008493349300_r73","doi-asserted-by":"crossref","first-page":"2378","DOI":"10.1002\/eji.200737594","article-title":"DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3(+) conventional T cells","volume":"37","author":"Baron","year":"2007","journal-title":"Eur. J. Immunol."},{"key":"2025021008493349300_r74","doi-asserted-by":"crossref","first-page":"4362","DOI":"10.4049\/jimmunol.1402384","article-title":"Regulatory T cells require TCR signaling for their suppressive function","volume":"194","author":"Schmidt","year":"2015","journal-title":"J. Immunol."},{"key":"2025021008493349300_r75","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1038\/ni.3004","article-title":"Continuous requirement for the TCR in regulatory T cell function","volume":"15","author":"Levine","year":"2014","journal-title":"Nat. Immunol."},{"key":"2025021008493349300_r76","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1038\/ni.2084","article-title":"Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation","volume":"12","author":"Beyer","year":"2011","journal-title":"Nat. Immunol."},{"key":"2025021008493349300_r77","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1038\/nature11581","article-title":"Novel Foxo1-dependent transcriptional programs control T(reg) cell function","volume":"491","author":"Ouyang","year":"2012","journal-title":"Nature"},{"key":"2025021008493349300_r78","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1038\/ni.1689","article-title":"Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor","volume":"10","author":"Kerdiles","year":"2009","journal-title":"Nat. Immunol."},{"key":"2025021008493349300_r79","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1038\/ni.3522","article-title":"Affinity for self antigen selects Treg cells with distinct functional properties","volume":"17","author":"Wyss","year":"2016","journal-title":"Nat. Immunol."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/208\/2\/384\/61464974\/ji2100506.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/208\/2\/384\/61464974\/ji2100506.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T08:50:00Z","timestamp":1739177400000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/208\/2\/384\/7924520"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1]]},"references-count":79,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2022,1,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.2100506","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,1]]},"published":{"date-parts":[[2022,1]]}}}