{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:19:26Z","timestamp":1792790366963,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,28]]},"group-title":"Immunology","reference-count":82,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["AI125997"],"award-info":[{"award-number":["AI125997"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["AI137004"],"award-info":[{"award-number":["AI137004"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["AI180128"],"award-info":[{"award-number":["AI180128"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["GM79465"],"award-info":[{"award-number":["GM79465"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Colton Center for Autoimmunity at New York University","id":[{"id":"https:\/\/ror.org\/0190ak572","id-type":"ROR","asserted-by":"crossref"}]},{"name":"American Society of Hematology","id":[{"id":"https:\/\/ror.org\/02nw48b86","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Multiple Sclerosis Society","id":[{"id":"https:\/\/ror.org\/03019wv17","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,28]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Pathogenic T helper 17 (pT\n                  <jats:sub>H<\/jats:sub>\n                  17) cells are a subset of CD4\n                  <jats:sup>+<\/jats:sup>\n                  T cells driving autoimmune diseases including multiple sclerosis (MS). Compared to homeostatic T\n                  <jats:sub>H<\/jats:sub>\n                  17 cells and other T\n                  <jats:sub>H<\/jats:sub>\n                  subsets, pT\n                  <jats:sub>H<\/jats:sub>\n                  17 have enhanced mitochondrial function and oxidative phosphorylation (OXPHOS) that supports their differentiation and pathogenic function. Here we identify Copper Transporter 1 (CTR1), encoded by\n                  <jats:italic>Slc31a1,<\/jats:italic>\n                  as essential for copper uptake in CD4\n                  <jats:sup>+<\/jats:sup>\n                  T cells, OXPHOS and pT\n                  <jats:sub>H<\/jats:sub>\n                  17 cell differentiation and function. While copper levels are known to be higher in the cerebrospinal fluid of patients with MS compared to healthy individuals, and excess copper contributes to oligodendrocyte loss in murine models of MS, the effect of copper on T cell function and pathogenicity in MS are unclear. We demonstrate that deletion of\n                  <jats:italic>Slc31a1<\/jats:italic>\n                  in CD4\n                  <jats:sup>+<\/jats:sup>\n                  T cells decreased intracellular copper levels, disrupting mitochondrial respiration and rewiring metabolism. These changes altered the epigenetic landscape of pT\n                  <jats:sub>H<\/jats:sub>\n                  17 cells by impairing DNA demethylation capacity, leading to hypermethylated DNA and altered chromatin accessibility at key binding sites for AP-1 transcription factors essential for pT\n                  <jats:sub>H<\/jats:sub>\n                  17 differentiation. As a result, CTR1-deficient T cells showed defective differentiation into pT\n                  <jats:sub>H<\/jats:sub>\n                  17 cells, with decreased production of IL-17A and expression of T\n                  <jats:sub>H<\/jats:sub>\n                  17 signature genes, while the differentiation of other CD4\n                  <jats:sup>+<\/jats:sup>\n                  T cell subsets remained largely unaffected. Moreover, T cell-specific deletion of\n                  <jats:italic>Slc31a1<\/jats:italic>\n                  protected mice from central nervous system (CNS) inflammation in the experimental autoimmune encephalomyelitis (EAE) model of MS by suppressing clonal expansion of autoreactive CD4\n                  <jats:sup>+<\/jats:sup>\n                  T cells. These findings establish copper as a critical regulator of pT\n                  <jats:sub>H<\/jats:sub>\n                  17 differentiation and function, revealing a previously unknown molecular link between copper homeostasis, metabolism and epigenetic regulation governing pT\n                  <jats:sub>H<\/jats:sub>\n                  17-mediated autoimmunity.\n                <\/jats:p>","DOI":"10.64898\/2026.09.22.747582","type":"posted-content","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T15:35:22Z","timestamp":1790609722000},"source":"Crossref","is-referenced-by-count":0,"title":["CTR1-mediated copper uptake orchestrates metabolic-epigenetic regulation of pathogenic T\n                  <sub>H<\/sub>\n                  17 cells in autoimmune disease"],"prefix":"10.64898","author":[{"given":"Lucile","family":"Noyer","sequence":"first","affiliation":[{"name":"Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liwei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miki","family":"Jishage","sequence":"additional","affiliation":[{"name":"Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxwell","family":"McDermott","sequence":"additional","affiliation":[{"name":"Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aidan T","family":"Pezacki","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Princeton University, NJ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony Y","family":"Tao","sequence":"additional","affiliation":[{"name":"Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravichandran","family":"Ramasamy","sequence":"additional","affiliation":[{"name":"Diabetes Research Program, Department of Medicine, NYU Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Stadtfeld","sequence":"additional","affiliation":[{"name":"Sanford I. Weill Department of Medicine, Sandra and Edward Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Princeton University, NJ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5431-8178","authenticated-orcid":false,"given":"Stefan","family":"Feske","sequence":"additional","affiliation":[{"name":"Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026100106500454000_2026.09.22.747582v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-025-01535-9"},{"key":"2026100106500454000_2026.09.22.747582v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-022-01387-9"},{"key":"2026100106500454000_2026.09.22.747582v1.3","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032414-112212"},{"key":"2026100106500454000_2026.09.22.747582v1.4","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aaw8014"},{"key":"2026100106500454000_2026.09.22.747582v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2019.01.019"},{"key":"2026100106500454000_2026.09.22.747582v1.6","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1103095"},{"key":"2026100106500454000_2026.09.22.747582v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtemb.2026.127819"},{"key":"2026100106500454000_2026.09.22.747582v1.8","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.adq8860"},{"key":"2026100106500454000_2026.09.22.747582v1.9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.14.7481"},{"key":"2026100106500454000_2026.09.22.747582v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-1119(00)00287-0"},{"key":"2026100106500454000_2026.09.22.747582v1.11","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.111057298"},{"key":"2026100106500454000_2026.09.22.747582v1.12","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0509929103"},{"key":"2026100106500454000_2026.09.22.747582v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09376-7"},{"key":"2026100106500454000_2026.09.22.747582v1.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2006.08.009"},{"key":"2026100106500454000_2026.09.22.747582v1.15","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2021.711227"},{"key":"2026100106500454000_2026.09.22.747582v1.16","doi-asserted-by":"publisher","DOI":"10.1126\/science.272.5265.1136"},{"key":"2026100106500454000_2026.09.22.747582v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.msard.2020.102426"},{"key":"2026100106500454000_2026.09.22.747582v1.18","doi-asserted-by":"publisher","DOI":"10.1007\/s12011-022-03148-z"},{"key":"2026100106500454000_2026.09.22.747582v1.19","doi-asserted-by":"publisher","DOI":"10.1111\/1523-1747.ep13077206"},{"key":"2026100106500454000_2026.09.22.747582v1.20","doi-asserted-by":"publisher","DOI":"10.1007\/s12011-022-03335-y"},{"key":"2026100106500454000_2026.09.22.747582v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2008.09.003"},{"key":"2026100106500454000_2026.09.22.747582v1.22","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06017-4"},{"key":"2026100106500454000_2026.09.22.747582v1.23","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aec2573"},{"key":"2026100106500454000_2026.09.22.747582v1.24","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2202736119"},{"key":"2026100106500454000_2026.09.22.747582v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2017.05.007"},{"key":"2026100106500454000_2026.09.22.747582v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2017.09.014"},{"key":"2026100106500454000_2026.09.22.747582v1.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.01.022"},{"key":"2026100106500454000_2026.09.22.747582v1.28","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05264-1"},{"key":"2026100106500454000_2026.09.22.747582v1.29","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20250185"},{"key":"2026100106500454000_2026.09.22.747582v1.30","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2017.03.019"},{"key":"2026100106500454000_2026.09.22.747582v1.31","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-020-0481-4"},{"key":"2026100106500454000_2026.09.22.747582v1.32","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-020-0432-9"},{"key":"2026100106500454000_2026.09.22.747582v1.33","doi-asserted-by":"publisher","DOI":"10.1038\/nature13180"},{"key":"2026100106500454000_2026.09.22.747582v1.34","doi-asserted-by":"publisher","DOI":"10.1128\/mcb.05722-11"},{"key":"2026100106500454000_2026.09.22.747582v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.110520"},{"key":"2026100106500454000_2026.09.22.747582v1.36","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201242889"},{"key":"2026100106500454000_2026.09.22.747582v1.37","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2013.04.018"},{"key":"2026100106500454000_2026.09.22.747582v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2010.12.014"},{"key":"2026100106500454000_2026.09.22.747582v1.39","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1401162"},{"key":"2026100106500454000_2026.09.22.747582v1.40","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-020-00287-8"},{"key":"2026100106500454000_2026.09.22.747582v1.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.114993"},{"key":"2026100106500454000_2026.09.22.747582v1.42","doi-asserted-by":"publisher","DOI":"10.1038\/srep16355"},{"key":"2026100106500454000_2026.09.22.747582v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.09.064"},{"key":"2026100106500454000_2026.09.22.747582v1.44","doi-asserted-by":"publisher","DOI":"10.1038\/nature08114"},{"key":"2026100106500454000_2026.09.22.747582v1.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.09.016"},{"key":"2026100106500454000_2026.09.22.747582v1.46","doi-asserted-by":"publisher","DOI":"10.1038\/nri3470"},{"key":"2026100106500454000_2026.09.22.747582v1.47","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20070994"},{"key":"2026100106500454000_2026.09.22.747582v1.48","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.351916"},{"key":"2026100106500454000_2026.09.22.747582v1.49","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.03.005"},{"key":"2026100106500454000_2026.09.22.747582v1.50","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2025.112315"},{"key":"2026100106500454000_2026.09.22.747582v1.51","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2024.06.008"},{"key":"2026100106500454000_2026.09.22.747582v1.52","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1311-3"},{"key":"2026100106500454000_2026.09.22.747582v1.53","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0846-z"},{"key":"2026100106500454000_2026.09.22.747582v1.54","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.16093"},{"key":"2026100106500454000_2026.09.22.747582v1.55","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.299313"},{"key":"2026100106500454000_2026.09.22.747582v1.56","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2020.01.006"},{"key":"2026100106500454000_2026.09.22.747582v1.57","doi-asserted-by":"publisher","DOI":"10.1186\/ar1801"},{"key":"2026100106500454000_2026.09.22.747582v1.58","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2025804118"},{"key":"2026100106500454000_2026.09.22.747582v1.59","doi-asserted-by":"publisher","DOI":"10.1007\/s12031-013-0026-4"},{"key":"2026100106500454000_2026.09.22.747582v1.60","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202100273RR"},{"key":"2026100106500454000_2026.09.22.747582v1.61","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.08.002"},{"key":"2026100106500454000_2026.09.22.747582v1.62","unstructured":"CRISPick, <https:\/\/portals.broadinstitute.org\/gppx\/crispick\/public> ("},{"key":"2026100106500454000_2026.09.22.747582v1.63","doi-asserted-by":"publisher","DOI":"10.1002\/cpim.62"},{"key":"2026100106500454000_2026.09.22.747582v1.64","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2006.285"},{"key":"2026100106500454000_2026.09.22.747582v1.65","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu170"},{"key":"2026100106500454000_2026.09.22.747582v1.66","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"2026100106500454000_2026.09.22.747582v1.67","unstructured":"DESeq2, <https:\/\/www.bioconductor.org\/packages\/release\/bioc\/vignettes\/DESeq2\/inst\/doc\/DESeq2.html> ("},{"key":"2026100106500454000_2026.09.22.747582v1.68","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118"},{"key":"2026100106500454000_2026.09.22.747582v1.69","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2015.12.004"},{"key":"2026100106500454000_2026.09.22.747582v1.70","unstructured":"Ingenuity Pathway Analysis, <https:\/\/digitalinsights.qiagen.com\/IPA> ("},{"key":"2026100106500454000_2026.09.22.747582v1.71","unstructured":"igraph, <https:\/\/igraph.org> ("},{"key":"2026100106500454000_2026.09.22.747582v1.72","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.2070"},{"key":"2026100106500454000_2026.09.22.747582v1.73","unstructured":"Dorado, <https:\/\/github.com\/nanoporetech\/dorado> ("},{"key":"2026100106500454000_2026.09.22.747582v1.74","unstructured":"Modkit, <https:\/\/github.com\/nanoporetech\/modkit> ("},{"key":"2026100106500454000_2026.09.22.747582v1.75","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2493-4"},{"key":"2026100106500454000_2026.09.22.747582v1.76","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1923"},{"key":"2026100106500454000_2026.09.22.747582v1.77","unstructured":"Sambamba, <https:\/\/lomereiter.github.io\/sambamba\/> ("},{"key":"2026100106500454000_2026.09.22.747582v1.78","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2008-9-9-r137"},{"key":"2026100106500454000_2026.09.22.747582v1.79","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btv145"},{"key":"2026100106500454000_2026.09.22.747582v1.80","unstructured":"DiffBind, <http:\/\/bioconductor.org\/packages\/release\/bioc\/html\/DiffBind.html> ("},{"key":"2026100106500454000_2026.09.22.747582v1.81","unstructured":"HOMER, <http:\/\/homer.ucsd.edu\/homer\/> ("},{"key":"2026100106500454000_2026.09.22.747582v1.82","unstructured":"TOBIAS, <https:\/\/github.com\/loosolab\/TOBIAS> ("}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.09.22.747582","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T14:20:40Z","timestamp":1790864440000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.09.22.747582"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,28]]},"references-count":82,"URL":"https:\/\/doi.org\/10.64898\/2026.09.22.747582","relation":{},"subject":[],"published":{"date-parts":[[2026,9,28]]},"subtype":"preprint"}}