{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T17:53:37Z","timestamp":1785866017746,"version":"3.56.0"},"reference-count":133,"publisher":"American Society for Clinical Investigation","issue":"18","license":[{"start":{"date-parts":[[2020,9,17]],"date-time":"2020-09-17T00:00:00Z","timestamp":1600300800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Netherlands Organization for Scientific Research","award":["VIDI grant 91714332"],"award-info":[{"award-number":["VIDI grant 91714332"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,9,17]]},"abstract":"<jats:p>\n                    Tregs are crucial for maintaining maternal immunotolerance against the semiallogeneic fetus. We investigated the elusive transcriptional profile and functional adaptation of human uterine Tregs (uTregs) during pregnancy. Uterine biopsies, from placental bed (materno-fetal interface) and incision site (control) and blood were obtained from women with uncomplicated pregnancies undergoing cesarean section. Tregs and CD4\n                    <jats:sup>+<\/jats:sup>\n                    non-Tregs were isolated for transcriptomic profiling by Cel-Seq2. Results were validated on protein and single cell levels by flow cytometry. Placental bed uTregs showed elevated expression of Treg signature markers, including FOXP3, CTLA-4, and TIGIT. Their transcriptional profile was indicative of late-stage effector Treg differentiation and chronic activation, with increased expression of immune checkpoints GITR, TNFR2, OX-40, and 4-1BB; genes associated with suppressive capacity (\n                    <jats:italic>HAVCR2<\/jats:italic>\n                    ,\n                    <jats:italic>IL10<\/jats:italic>\n                    ,\n                    <jats:italic>LAYN<\/jats:italic>\n                    , and\n                    <jats:italic>PDCD1<\/jats:italic>\n                    ); and transcription factors\n                    <jats:italic>MAF<\/jats:italic>\n                    ,\n                    <jats:italic>PRDM1<\/jats:italic>\n                    ,\n                    <jats:italic>BATF<\/jats:italic>\n                    , and\n                    <jats:italic>VDR<\/jats:italic>\n                    . uTregs mirrored non-Treg Th1 polarization and tissue residency. The particular transcriptional signature of placental bed uTregs overlapped strongly with that of tumor-infiltrating Tregs and was remarkably pronounced at the placental bed compared with uterine control site. In conclusion, human uTregs acquire a differentiated effector Treg profile similar to tumor-infiltrating Tregs, specifically at the materno-fetal interface. This introduces the concept of site-specific transcriptional adaptation of Tregs within 1 organ.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.137926","type":"journal-article","created":{"date-parts":[[2020,8,18]],"date-time":"2020-08-18T12:02:13Z","timestamp":1597752133000},"source":"Crossref","is-referenced-by-count":39,"title":["Human Tregs at the materno-fetal interface show site-specific adaptation reminiscent of tumor Tregs"],"prefix":"10.1172","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3835-6374","authenticated-orcid":true,"given":"Judith","family":"Wienke","sequence":"first","affiliation":[{"name":"Center for Translational Immunology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Brouwers","sequence":"additional","affiliation":[{"name":"Wilhelmina Children\u2019s Hospital Birth Center,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leone M.","family":"van der Burg","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5298-4852","authenticated-orcid":true,"given":"Michal","family":"Mokry","sequence":"additional","affiliation":[{"name":"Regenerative Medicine Utrecht,"},{"name":"Laboratory of Clinical Chemistry and Hematology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rianne C.","family":"Scholman","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter G.J.","family":"Nikkels","sequence":"additional","affiliation":[{"name":"Department of Pathology, Wilhelmina Children\u2019s Hospital, University Medical Center Utrecht, Utrecht University, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1305-3825","authenticated-orcid":true,"given":"Bas B.","family":"van Rijn","sequence":"additional","affiliation":[{"name":"Wilhelmina Children\u2019s Hospital Birth Center,"},{"name":"Obstetrics and Fetal Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Femke","family":"van Wijk","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology,"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2020,9,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aas9673"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aav5581"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.10.026"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.08.078"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3589"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0016245"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.09.020"},{"key":"B8","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2014.00294","article-title":"Characterization and functional properties of gastric tissue-resident memory T cells from children, adults, and the elderly","volume":"5","author":"Booth","year":"2014","journal-title":"Front Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2016.36"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1172\/JCI57175"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/nri2785"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.10.054"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3799"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0148351"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.01.001"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/nature11132"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.26322"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aat5861"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/nri3605"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2002"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4008"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0351-z"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aaf7471"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aao4310"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.10.021"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.10.032"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.05.060"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.04.008"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2009.03.019"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2008.03.018"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2012.11.002"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2006"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2017.07.008"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2018.04.003"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-11-392324"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1731"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2015.74"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1616710113"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1126\/science.1172702"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/nature07674"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3053"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1126\/science.aac4263"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1172\/JCI57456"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.08.012"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.06.014"},{"key":"B46","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2018.00883","article-title":"Emerging Functions of Regulatory T Cells in Tissue Homeostasis","volume":"9","author":"Sharma","year":"2018","journal-title":"Front Immunol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/nri3361"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.64"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1177\/0192623313482205"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1038\/420265a"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1700114"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1038\/nature11462"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1038\/ni1037"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1202413"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-03191-0"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1093\/molehr\/gah044"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.2007.03397.x"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.109.081208"},{"key":"B59","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1111\/j.1600-0897.2011.01046.x","article-title":"Maternal Foxp3 expressing CD4+ CD25+ and CD4+ CD25- regulatory T-cell populations are enriched in human early normal pregnancy decidua: a phenotypic study of paired decidual and peripheral blood samples","volume":"66 Suppl 1","author":"Dimova","year":"2011","journal-title":"Am J Reprod Immunol"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1016\/j.jri.2009.05.003"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.8.5737"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2009.08.009"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.2004.02441.x"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2567.2004.01869.x"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1111\/aji.12970"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1111\/aji.12546"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejogrb.2010.11.007"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2007.03.037"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0897.2007.00489.x"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0901154"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1401343111"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.02.012"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa9420"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.06.079"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3085"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3646"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2084"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.08.068"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3085"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a028506"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0902070"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.2337\/db14-1322"},{"key":"B83","doi-asserted-by":"crossref","DOI":"10.1038\/msb.2012.56","article-title":"PLAU inferred from a correlation network is critical for suppressor function of regulatory T cells","volume":"8","author":"He","year":"2012","journal-title":"Mol Syst Biol"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1000082"},{"key":"B85","unstructured":"Beyer M, Classen S, Chemnitz J, Gaarz A, Schultze J. Regulatory T-cell comittment is ensured by inhibition of the global gene regulator SATB1. NCBI Gene Expression Omibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE16835 Published May 31, 2017. Accessed August 26, 2020"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2017.94"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200636575"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1767"},{"key":"B89","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2018.01344","article-title":"Common Features of Regulatory T Cell Specialization During Th1 Responses","volume":"9","author":"Littringer","year":"2018","journal-title":"Front Immunol"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20060956"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2008.12.022"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-04-1632"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032712-095948"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.08.021"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-16-0193"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-0554"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad0501"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.05.035"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1720113115"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1810580115"},{"key":"B101","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2018.02165","article-title":"Notch and NF-\u03baB: Coach and Players of Regulatory T-Cell Response in Cancer","volume":"9","author":"Ferrandino","year":"2018","journal-title":"Front Immunol"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1016\/bs.ai.2016.08.002"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20070081"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.1159\/000129639"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0803177"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.4.2367"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1507977112"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.04.109"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27188"},{"key":"B110","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2389"},{"key":"B111","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1003099"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2014.92"},{"key":"B113","doi-asserted-by":"publisher","DOI":"10.1093\/molehr\/gal032"},{"key":"B114","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2018.01934","article-title":"Clonally Expanded Decidual Effector Regulatory T Cells Increase in Late Gestation of Normal Pregnancy, but Not in Preeclampsia, in Humans","volume":"9","author":"Tsuda","year":"2018","journal-title":"Front Immunol"},{"key":"B115","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2010.101"},{"key":"B116","doi-asserted-by":"publisher","DOI":"10.1111\/aji.12524"},{"issue":"11","key":"B117","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1016\/S0025-6196(11)60669-1","article-title":"Cancer and pregnancy: parallels in growth, invasion, and immune modulation and implications for cancer therapeutic agents","volume":"84","author":"Holtan","year":"2009","journal-title":"Mayo Clin Proc"},{"key":"B118","doi-asserted-by":"publisher","DOI":"10.1172\/JCI31537"},{"issue":"5","key":"B119","first-page":"81","article-title":"Tumor-infiltrating regulatory T cells: origins and features","volume":"7","author":"Deng","year":"2018","journal-title":"Am J Clin Exp Immunol"},{"key":"B120","doi-asserted-by":"publisher","DOI":"10.1172\/JCI38714"},{"key":"B121","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0694-x"},{"key":"B122","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1801368"},{"key":"B123","doi-asserted-by":"publisher","DOI":"10.1172\/JCI125917"},{"key":"B124","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4437"},{"key":"B125","doi-asserted-by":"publisher","DOI":"10.1016\/j.jri.2014.09.053"},{"issue":"1","key":"B126","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1111\/j.1600-0897.2009.00763.x","article-title":"Imbalance of T-cell transcription factors contributes to the Th1 type immunity predominant in pre-eclampsia","volume":"63","author":"Jianjun","year":"2010","journal-title":"Am J Reprod Immunol"},{"key":"B127","doi-asserted-by":"publisher","DOI":"10.1097\/HJH.0000000000000964"},{"key":"B128","doi-asserted-by":"publisher","DOI":"10.1002\/art.39418"},{"key":"B129","doi-asserted-by":"crossref","DOI":"10.1186\/s13059-016-0938-8","article-title":"CEL-Seq2: sensitive highly-multiplexed single-cell RNA-Seq","volume":"17","author":"Hashimshony","year":"2016","journal-title":"Genome Biol"},{"key":"B130","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp698"},{"issue":"Web Server issue","key":"B131","doi-asserted-by":"crossref","first-page":"W305","DOI":"10.1093\/nar\/gkp427","article-title":"ToppGene Suite for gene list enrichment analysis and candidate gene prioritization","volume":"37","author":"Chen","year":"2009","journal-title":"Nucleic Acids Res"},{"key":"B132","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"B133","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/30.1.207"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/137926\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:53:08Z","timestamp":1779151988000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/137926"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,17]]},"references-count":133,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2020,9,17]]},"published-print":{"date-parts":[[2020,9,17]]}},"alternative-id":["10.1172\/jci.insight.137926"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.137926","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/820753","asserted-by":"object"}]},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,17]]},"article-number":"e137926"}}