{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T18:46:18Z","timestamp":1782758778658,"version":"3.54.5"},"reference-count":76,"publisher":"American Society for Clinical Investigation","issue":"11","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Netherlands Organization for Scientific Research","award":["91618150"],"award-info":[{"award-number":["91618150"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,6,8]]},"abstract":"<jats:p>\n                    Human CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells utilize nutrients, including lipids, to support their activation and polarization. Considering the pivotal role of lipoproteins in lipid transport, we reasoned that lipoprotein uptake and processing could effect CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell function. Here, we demonstrate that activation of human CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells induced expression of LDL receptor (LDLR) to facilitate LDLR-mediated endocytosis of LDL. Degradation of surface LDLR on CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells with PCSK9 hampered activation and proliferation of the cells. Lipoprotein deprivation or blocking of lysosomal cholesterol egress impaired activation of mechanistic target of rapamycin complex 1 (mTORC1), affecting CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell activation and proliferation. Furthermore, lipoprotein deprivation of cultured primary CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells lead to reduced expression of c-MAF and FOXP3, key transcription factors for IL-10, accompanied by reduced IL-10 secretion. The pivotal role of LDLR-mediated lipoprotein uptake for mTORC1 activity, c-MAF and FOXP3 expression, and IL-10 secretion was confirmed using LDLR-dysfunctional CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells from patients with homozygous familial hypercholesterolemia. Our study offers valuable insights into the lipoprotein metabolism of human CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells and their reliance on the LDLR pathway for activation and polarization, a feature that may be leveraged to modulate CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell function.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.198505","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T16:54:14Z","timestamp":1780937654000},"source":"Crossref","is-referenced-by-count":0,"title":["LDL receptor\u2013mediated lipoprotein uptake fuels human CD4+ T cell polarization toward a c-MAF\/IL-10\u2013 and FOXP3-driven phenotype"],"prefix":"10.1172","volume":"11","author":[{"given":"Angela","family":"Markovska","sequence":"first","affiliation":[{"name":"Center for Translational Immunology, University Medical Centre Utrecht, Utrecht, Netherlands."},{"name":"Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niels S.","family":"van Heusden","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology, University Medical Centre Utrecht, Utrecht, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dagmar","family":"Duijzer","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology, University Medical Centre Utrecht, Utrecht, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandra","family":"Bodel\u00f3n","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology, University Medical Centre Utrecht, Utrecht, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greta","family":"Rogani","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology, University Medical Centre Utrecht, Utrecht, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enric","family":"Mocholi","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine, University Medical Center Utrecht, Regenerative Medicine Center, University Medical Center Utrecht, Utrecht, Netherlands."},{"name":"Department of Ciencias Biom\u00e9dicas, Universidad Cardenal Herrera CEU, Valencia, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edwin C.A.","family":"Stigter","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine, University Medical Center Utrecht, Oncode Institute, Utrecht, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Can","family":"Gulersonmez","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine, University Medical Center Utrecht, Oncode Institute, Utrecht, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0014-5571","authenticated-orcid":true,"given":"Sander","family":"Kooijman","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonie","family":"Van der Zee","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Laboratory, Erasmus MC Cardiovascular Institute, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monique T.","family":"Mulder","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Laboratory, Erasmus MC Cardiovascular Institute, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanine E.","family":"Roeters van Lennep","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Laboratory, Erasmus MC Cardiovascular Institute, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8455-4988","authenticated-orcid":true,"given":"Patrick C.N.","family":"Rensen","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorg","family":"van Loosdregt","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology, University Medical Centre Utrecht, Utrecht, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastiaan J.","family":"Vastert","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology, University Medical Centre Utrecht, Utrecht, Netherlands."},{"name":"Department of Pediatric Rheumatology and Immunology, University Medical Center Utrecht, Utrecht, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noam","family":"Zelcer","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry, Amsterdam UMC \u2014 location AMC, University of Amsterdam, Amsterdam, Netherlands."},{"name":"Amsterdam Gastroenterology, Endocrinology, and Metabolism Institute, Amsterdam UMC, Amsterdam, Netherlands."},{"name":"Amsterdam Cardiovascular Sciences Institute, Amsterdam UMC, Amsterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2590-1692","authenticated-orcid":true,"given":"Marianne","family":"Boes","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology, University Medical Centre Utrecht, Utrecht, Netherlands."},{"name":"Pediatrics Department, University Medical Center, Utrecht, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1997-8060","authenticated-orcid":true,"given":"Henk S.","family":"Schipper","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology, University Medical Centre Utrecht, Utrecht, Netherlands."},{"name":"Department of Pediatric Cardiology, Sophia Children\u2019s Hospital, Erasmus Medical Center, Rotterdam, Netherlands."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,6,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00247"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2016.09.003"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-024-01148-8"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2016.10.009"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2021.12.012"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00540"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01949"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-020-0301-1"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-020-0379-5"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-025-01262-1"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.05.016"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.01.022"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1020422"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.123.319674"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-022-01125-5"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.12.022"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1186\/s43556-024-00218-7"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines9080985"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.vph.2018.08.002"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2022.845942"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2013.06.006"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.202202011"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2012.01152.x"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/nri3198"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2017.04.005"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2020.11.016"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1126\/science.aag1417"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1126\/science.abg6621"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2011.04.013"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2020.00010"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4315"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-04-211417"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1186\/s12944-016-0390-5"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2004.09.018"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.08.021"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.C066712"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2019.09.022"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1097\/MOL.0000000000000894"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(07)38006-3"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12152-2"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2020.09.001"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-08332-9"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/s41385-022-00487-x"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0900123"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-018-0083-5"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2017.11.008"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1002980"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2014.09.020"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2022.03.014"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/S1357-2725(99)00014-X"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.05.020"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2020.10.022"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1007\/s10238-022-00939-5"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3704"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.04.052"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20201311"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2019.04.002"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1038\/nature17412"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-024-01377-z"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.5b00213"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1002\/1521-4141(200003)30:3<954::AID-IMMU954>3.0.CO;2-Y"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2010.10.002"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1016\/j.sjbs.2022.02.002"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2014.01.022"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-15546-8"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-17179-4"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1038\/srep46348"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2018.3510"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-022-00740-9"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1126\/science.290.5500.2295"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1007\/s13238-021-00821-2"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2021.639727"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.ado2768"},{"key":"B74"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-11-395"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22975-7"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/198505\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T18:25:35Z","timestamp":1782757535000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/198505"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,8]]},"references-count":76,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,4,23]]},"published-print":{"date-parts":[[2026,6,8]]}},"alternative-id":["10.1172\/jci.insight.198505"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.198505","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,8]]},"article-number":"e198505"}}