{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T14:32:02Z","timestamp":1790778722385,"version":"4.1.0"},"reference-count":114,"publisher":"American Society for Clinical Investigation","issue":"11","license":[{"start":{"date-parts":[[2023,6,13]],"date-time":"2023-06-13T00:00:00Z","timestamp":1686614400000},"content-version":"vor","delay-in-days":5,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The National Health and Medical Research Council of Australia","award":["Project Grant APP1099461"],"award-info":[{"award-number":["Project Grant APP1099461"]}]},{"name":"The National Health and Medical Research Council of Australia","award":["Investigator Grant APP1198172"],"award-info":[{"award-number":["Investigator Grant APP1198172"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,6,8]]},"abstract":"<jats:p>\n                    Progesterone (P4) is essential for embryo implantation, but the extent to which the pro-gestational effects of P4 depend on the maternal immune compartment is unknown. Here, we investigate whether regulatory T cells (Treg cells) act to mediate luteal phase P4 effects on uterine receptivity in mice. P4 antagonist RU486 administered to mice on days 1.5 and 3.5 postcoitum to model luteal phase P4 deficiency caused fewer CD4\n                    <jats:sup>+<\/jats:sup>\n                    Foxp3\n                    <jats:sup>+<\/jats:sup>\n                    Treg cells and impaired Treg functional competence, along with dysfunctional uterine vascular remodeling and perturbed placental development in midgestation. These effects were linked with fetal loss and fetal growth restriction, accompanied by a Th1\/CD8-skewed T cell profile. Adoptive transfer at implantation of Treg cells \u2014 but not conventional T cells \u2014 alleviated fetal loss and fetal growth restriction by mitigating adverse effects of reduced P4 signaling on uterine blood vessel remodeling and placental structure and by restoring maternal T cell imbalance. These findings demonstrate an essential role for Treg cells in mediating P4 effects at implantation and indicate that Treg cells are a sensitive and critical effector mechanism through which P4 drives uterine receptivity to support robust placental development and fetal growth.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.162995","type":"journal-article","created":{"date-parts":[[2023,5,16]],"date-time":"2023-05-16T13:36:12Z","timestamp":1684244172000},"source":"Crossref","is-referenced-by-count":50,"title":["Regulatory T cells are paramount effectors in progesterone regulation of embryo implantation and fetal growth"],"prefix":"10.1172","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3009-3442","authenticated-orcid":true,"given":"Ella S.","family":"Green","sequence":"first","affiliation":[{"name":"Robinson Research Institute, School of Biomedicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3141-2521","authenticated-orcid":true,"given":"Lachlan M.","family":"Moldenhauer","sequence":"additional","affiliation":[{"name":"Robinson Research Institute, School of Biomedicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly M.","family":"Groome","sequence":"additional","affiliation":[{"name":"Robinson Research Institute, School of Biomedicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4831-7950","authenticated-orcid":true,"given":"David J.","family":"Sharkey","sequence":"additional","affiliation":[{"name":"Robinson Research Institute, School of Biomedicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0923-0553","authenticated-orcid":true,"given":"Peck Y.","family":"Chin","sequence":"additional","affiliation":[{"name":"Robinson Research Institute, School of Biomedicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0943-9453","authenticated-orcid":true,"given":"Alison S.","family":"Care","sequence":"additional","affiliation":[{"name":"Robinson Research Institute, School of Biomedicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1538-4604","authenticated-orcid":true,"given":"Rebecca L.","family":"Robker","sequence":"additional","affiliation":[{"name":"Robinson Research Institute, School of Biomedicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaun R.","family":"McColl","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9967-0084","authenticated-orcid":true,"given":"Sarah A.","family":"Robertson","sequence":"additional","affiliation":[{"name":"Robinson Research Institute, School of Biomedicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2023,6,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.9.18.2266"},{"issue":"8","key":"B2","doi-asserted-by":"crossref","first-page":"3472","DOI":"10.1172\/JCI60561","article-title":"Macrophages regulate corpus luteum development during embryo implantation in mice","volume":"123","author":"Care","year":"2013","journal-title":"J Clin Invest"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.ogc.2014.10.003"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra000763"},{"key":"B5","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.placenta.2017.07.012","article-title":"Global pregnancy collaboration symposium: prepregnancy and very early pregnancy antecedents of adverse pregnancy outcomes: overview and recommendations","volume":"60","author":"Roberts","year":"2017","journal-title":"Placenta"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2018.04.001"},{"key":"B7","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.placenta.2017.06.005","article-title":"Emerging role for dysregulated decidualization in the genesis of preeclampsia","volume":"60","author":"Conrad","year":"2017","journal-title":"Placenta"},{"issue":"198","key":"B8","article-title":"Progesterone-related immune modulation of pregnancy and labor","volume":"10","author":"Shah","year":"2019","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3160"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1172\/JCI122182"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1949.02910160013004"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/S1472-6483(10)60300-8"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/des367"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2010.08.009"},{"key":"B15","article-title":"Pre-eclampsia: pathophysiology and clinical implications","volume":"366","author":"Burton","year":"2019","journal-title":"BMJ"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.118.12043"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2007.12.001"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2022.104400"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201445404"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2019.00096"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9378(99)70239-5"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1053\/j.semperi.2014.10.004"},{"key":"B23","first-page":"332","article-title":"Intrauterine growth retardation (IUGR): epidemiology and etiology","volume":"6 Suppl 3","author":"Romo","year":"2009","journal-title":"Pediatr Endocrinol Rev"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3109\/14767058.2012.715006"},{"issue":"5","key":"B25","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1093\/molehr\/gal032","article-title":"Primary unexplained infertility is associated with reduced expression of the T-regulatory cell transcription factor Foxp3 in endometrial tissue","volume":"12","author":"Jasper","year":"2006","journal-title":"Mol Hum Reprod"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.jri.2014.09.053"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/der301"},{"issue":"1","key":"B28","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1111\/cei.12693","article-title":"Differentiation of ICOS+ and ICOS\u2212 recent thymic emigrant regulatory T cells (RTE Tregs) during normal pregnancy, pre-eclampsia and HELLP syndrome","volume":"183","author":"Wagner","year":"2016","journal-title":"Clin Exp Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2008.07.032"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2012.33"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.jri.2014.04.001"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0901154"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aan2263"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.107874"},{"issue":"1082","key":"B35","article-title":"Analysis of TCR repertoire and PD-1 expression in decidual and peripheral CD8+ T cells reveals distinct immune mechanisms in miscarriage and preeclampsia","volume":"11","author":"Morita","year":"2020","journal-title":"Front Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/ni1037"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1202413"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/nature11462"},{"issue":"1","key":"B39","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.chom.2011.06.005","article-title":"Foxp3+ regulatory T cell expansion required for sustaining pregnancy compromises host defense against prenatal bacterial pathogens","volume":"10","author":"Rowe","year":"2011","journal-title":"Cell Host Microbe"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2017.41"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20051511"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1001749107"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/srep13938"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0042301"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2009.04.010"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0897.1999.tb00464.x"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00478"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.118.10858"},{"issue":"8","key":"B49","doi-asserted-by":"crossref","first-page":"R884","DOI":"10.1152\/ajpregu.00154.2015","article-title":"An increased population of regulatory T cells improves the pathophysiology of placental ischemia in a rat model of preeclampsia","volume":"309","author":"Cornelius","year":"2015","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1003919"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201142317"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1210\/en.2010-0426"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1111\/aji.13084"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.8.5737"},{"issue":"9","key":"B55","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1016\/j.celrep.2019.04.109","article-title":"Three types of functional regulatory T cells control T cell responses at the human maternal-fetal interface","volume":"27","author":"Salvany-Celades","year":"2019","journal-title":"Cell Rep"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod.110.088591"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/1043-2760(91)90030-Q"},{"key":"B58"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsbmb.2014.11.023"},{"issue":"3","key":"B60","doi-asserted-by":"crossref","first-page":"647","DOI":"10.4049\/jimmunol.1900084","article-title":"Thymus-derived regulatory T cells exhibit Foxp3 epigenetic modification and phenotype attenuation after mating in mice","volume":"203","author":"Moldenhauer","year":"2019","journal-title":"J Immunol"},{"issue":"4","key":"B61","doi-asserted-by":"crossref","DOI":"10.1095\/biolreprod.115.128694","article-title":"Unstable Foxp3+ regulatory T cells and altered dendritic cells are associated with lipopolysaccharide-induced fetal loss in pregnant interleukin 10-deficient mice","volume":"93","author":"Prins","year":"2015","journal-title":"Biol Reprod"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0804018"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.168.3.1087"},{"issue":"3","key":"B64","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1189\/jlb.1012491","article-title":"The intracellular progesterone receptor regulates CD4+ T cells and T cell-dependent antibody responses","volume":"93","author":"Hughes","year":"2013","journal-title":"J Leukoc Biol"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-95213-1"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.05.031"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2018.00570"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.20981"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1530\/REP-20-0007"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1016\/S1472-6483(10)60649-9"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-020-00807-y"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a023143"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1210\/me.2002-0270"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/deab262"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-1040-z"},{"issue":"11","key":"B76","doi-asserted-by":"crossref","DOI":"10.1111\/cpr.13128","article-title":"Deciphering mouse uterine receptivity for embryo implantation at single-cell resolution","volume":"54","author":"Yang","year":"2021","journal-title":"Cell Prolif"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.4.2572"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006736"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2009.138"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1302678"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3331"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmab003"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1530\/jrf.0.0640409"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02890"},{"issue":"3","key":"B85","article-title":"Fresh versus frozen embryo transfers in assisted reproduction","volume":"3","author":"Wong","year":"2017","journal-title":"Cochrane Database Syst Rev"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1053\/plac.2000.0594"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2017.01.114"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0145982"},{"key":"B89","doi-asserted-by":"crossref","DOI":"10.1155\/2019\/6721531","article-title":"T cell-derived IL-17A induces vascular dysfunction via perivascular fibrosis formation and dysregulation of \u00b7NO\/cGMP signaling","volume":"2019","author":"Sch\u00fcler","year":"2019","journal-title":"Oxid Med Cell Longev"},{"key":"B90","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2014.00504","article-title":"T cells in vascular inflammatory diseases","volume":"5","author":"Lintermans","year":"2014","journal-title":"Front Immunol"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00117.2016"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.835625"},{"issue":"2","key":"B93","doi-asserted-by":"crossref","first-page":"E181","DOI":"10.1073\/pnas.1617115114","article-title":"Glucocorticoid receptor in T cells mediates protection from autoimmunity in pregnancy","volume":"114","author":"Engler","year":"2017","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"11","key":"B94","doi-asserted-by":"crossref","first-page":"1544","DOI":"10.1111\/1471-0528.13294","article-title":"Membrane progesterone receptors in human regulatory T cells: a reality in pregnancy","volume":"122","author":"Areia","year":"2015","journal-title":"BJOG"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1096\/fj.11-193334"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.201302618"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.21.12021"},{"issue":"2","key":"B98","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1111\/j.1365-2567.2006.02559.x","article-title":"Murine pregnancy leads to reduced proliferation of maternal thymocytes and decreased thymic emigration","volume":"121","author":"Zoller","year":"2007","journal-title":"Immunology"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1016\/0167-5699(94)90212-7"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2015.51"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-88508-w"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2008-0460"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dex252"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2021.02.010"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.1210\/er.2006-0022"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.1016\/j.jri.2010.01.008"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1093\/molehr\/gaac043"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.640907"},{"issue":"1293","key":"B109","article-title":"Progesterone modulation of pregnancy-related immune responses","volume":"9","author":"Shah","year":"2018","journal-title":"Front Immunol"},{"key":"B110","article-title":"Steroids, pregnancy and fetal development","volume":"10","author":"Solano","year":"2019","journal-title":"Front Immunol"},{"key":"B111","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0220450"},{"issue":"9","key":"B112","article-title":"Luteal phase in assisted reproductive technology","volume":"2","author":"Tesarik","year":"2020","journal-title":"Front Reprod Health"},{"key":"B113","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgab753"},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2019.12.006"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/162995\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T21:54:24Z","timestamp":1779141264000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/162995"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,8]]},"references-count":114,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,6,8]]},"published-print":{"date-parts":[[2023,6,8]]}},"alternative-id":["10.1172\/jci.insight.162995"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.162995","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,8]]},"article-number":"e162995"}}