{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T23:07:36Z","timestamp":1788908856362,"version":"build-2803163510"},"reference-count":24,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T00:00:00Z","timestamp":1787961600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01DK128143"],"award-info":[{"award-number":["R01DK128143"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32AI089474"],"award-info":[{"award-number":["T32AI089474"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Many autoimmune diseases exhibit a female sex bias in prevalence and severity, yet the mechanisms for this remain unclear. 17\u03b2-estradiol (E2) is a steroid sex hormone with established immunomodulatory roles in CD4+ T cells, which express the nuclear estrogen receptors ER\u03b1 and ER\u03b2. Autoimmune disease patients exhibit reductions in ER\u03b2 expression, suggesting that dysregulated E2 signaling contributes to inflammation. We previously identified a novel role for ER\u03b2 in promoting the TGF-\u03b2-dependent differentiation of Foxp3+ Tregs, supporting the idea that ER\u03b2 has anti-inflammatory functions. In this study, we investigated the functional role of ER\u03b2 in effector T cells, which drive pathogenesis of many autoimmune diseases. CD4+ T cells isolated from mice globally deficient in ER\u03b2 (ER\u03b2-KO) showed enhanced proliferation and polarization to Th1 and Th17 populations ex vivo and conferred more severe inflammation and experimental colitis when transferred to immunodeficient Rag-KO mice. Treatment of ER\u03b2-KO T cells ex vivo with anti-CD3\/28 and PMA\/ionomycin resulted in robust activation-induced production of Th17-associated cytokines, suggesting that ER\u03b2 normally functions to restrain Th17. Collectively, our data support a model in which reduced ER\u03b2 expression may contribute to loss of immunoregulatory signaling and enhanced T cell\u2013driven inflammation.<\/jats:p>","DOI":"10.1093\/jimmun\/vkag238","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T22:35:38Z","timestamp":1788906938000},"source":"Crossref","is-referenced-by-count":0,"title":["Estrogen receptor beta limits T cell\u2013mediated inflammation to maintain immune homeostasis"],"prefix":"10.1093","volume":"215","author":[{"given":"Alyssia V","family":"Broncano","sequence":"first","affiliation":[{"name":"Department of Pathology, Case Western Reserve University School of Medicine , Cleveland, OH,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah K","family":"McNeer","sequence":"additional","affiliation":[{"name":"Department of Pathology, Case Western Reserve University School of Medicine , Cleveland, OH,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah M","family":"Stark","sequence":"additional","affiliation":[{"name":"Department of Pathology, Case Western Reserve University School of Medicine , Cleveland, OH,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5638-0861","authenticated-orcid":false,"given":"Alicia","family":"Santin","sequence":"additional","affiliation":[{"name":"Department of Pathology, Case Western Reserve University School of Medicine , Cleveland, OH,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline M","family":"Schlessman","sequence":"additional","affiliation":[{"name":"Department of Pathology, Case Western Reserve University School of Medicine , Cleveland, OH,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle L","family":"Raymond","sequence":"additional","affiliation":[{"name":"Department of Pathology, Case Western Reserve University School of Medicine , Cleveland, OH,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William B","family":"Tran","sequence":"additional","affiliation":[{"name":"Department of Pathology, Case Western Reserve University School of Medicine , Cleveland, OH,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan P","family":"Hall","sequence":"additional","affiliation":[{"name":"Department of Pathology, Case Western Reserve University School of Medicine , Cleveland, OH,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian D","family":"Kocinski","sequence":"additional","affiliation":[{"name":"Department of Pathology, Case Western Reserve University School of Medicine , Cleveland, OH,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas P","family":"Ziats","sequence":"additional","affiliation":[{"name":"Department of Pathology, Case Western Reserve University School of Medicine , Cleveland, OH,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6864-0384","authenticated-orcid":false,"given":"Wendy A","family":"Goodman","sequence":"additional","affiliation":[{"name":"Department of Pathology, Case Western Reserve University School of Medicine , Cleveland, OH,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,9,8]]},"reference":[{"key":"2026090818353387800_vkag238-B1","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1097\/BOR.0000000000000564","article-title":"Sex bias in autoimmunity","volume":"31","author":"Billi","year":"2019","journal-title":"Curr Opin Rheumatol"},{"key":"2026090818353387800_vkag238-B2","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1038\/nri.2016.90","article-title":"Sex differences in immune responses","volume":"16","author":"Klein","year":"2016","journal-title":"Nat Rev Immunol"},{"key":"2026090818353387800_vkag238-B3","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1146\/annurev-immunol-101320-125133","article-title":"Sex differences in immunity","volume":"40","author":"Wilkinson","year":"2022","journal-title":"Annu Rev Immunol"},{"key":"2026090818353387800_vkag238-B4","doi-asserted-by":"publisher","first-page":"635","DOI":"10.3389\/fimmu.2015.00635","article-title":"The immune system is a natural target for estrogen action: opposing effects of estrogen in two prototypical autoimmune diseases","volume":"6","author":"Khan","year":"2015","journal-title":"Front Immunol"},{"key":"2026090818353387800_vkag238-B5","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1186\/s12948-016-0048-x","article-title":"How pregnancy can affect autoimmune diseases progression?","volume":"14","author":"Piccinni","year":"2016","journal-title":"Clin Mol Allergy"},{"key":"2026090818353387800_vkag238-B6","doi-asserted-by":"publisher","first-page":"1153","DOI":"10.1136\/gutjnl-2012-302362","article-title":"Oral contraceptives, reproductive factors and risk of inflammatory bowel disease","volume":"62","author":"Khalili","year":"2013","journal-title":"Gut"},{"key":"2026090818353387800_vkag238-B7","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1111\/apt.16647","article-title":"Use of contraceptives and risk of inflammatory bowel disease: a nested case-control study","volume":"55","author":"Pasvol","year":"2022","journal-title":"Aliment Pharmacol Ther"},{"key":"2026090818353387800_vkag238-B8","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1210\/me.2004-0486","article-title":"Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes","volume":"19","author":"Bjornstrom","year":"2005","journal-title":"Mol Endocrinol"},{"key":"2026090818353387800_vkag238-B9","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/bs.apcsb.2019.01.001","article-title":"Estrogen receptor signaling mechanisms","volume":"116","author":"Fuentes","year":"2019","journal-title":"Adv Protein Chem Struct Biol"},{"key":"2026090818353387800_vkag238-B10","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1002\/rmb2.12006","article-title":"Molecular mechanism of estrogen-estrogen receptor signaling","volume":"16","author":"Ya\u015far","year":"2017","journal-title":"Reprod Med Biol"},{"key":"2026090818353387800_vkag238-B11","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1007\/s12016-010-8203-5","article-title":"Estrogen receptors in immunity and autoimmunity","volume":"40","author":"Cunningham","year":"2011","journal-title":"Clin Rev Allergy Immunol"},{"key":"2026090818353387800_vkag238-B12","doi-asserted-by":"publisher","first-page":"17166","DOI":"10.1073\/pnas.2002266117","article-title":"Impaired estrogen signaling underlies regulatory T cell loss-of-function in the chronically inflamed intestine","volume":"117","author":"Goodman","year":"2020","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026090818353387800_vkag238-B13","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/s13293-016-0057-y","article-title":"Low expression of estrogen receptor beta in T lymphocytes and high serum levels of anti-estrogen receptor alpha antibodies impact disease activity in female patients with systemic lupus erythematosus","volume":"7","author":"Maselli","year":"2016","journal-title":"Biol Sex Differ"},{"key":"2026090818353387800_vkag238-B14","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aap9415","article-title":"Estrogen receptor alpha contributes to T cell-mediated autoimmune inflammation by promoting T cell activation and proliferation","volume":"11","author":"Mohammad","year":"2018","journal-title":"Sci Signal"},{"key":"2026090818353387800_vkag238-B15","doi-asserted-by":"publisher","first-page":"2183","DOI":"10.2147\/OTT.S236532","article-title":"ERalpha, a key target for cancer therapy: a review","volume":"13","author":"Liu","year":"2020","journal-title":"Onco Targets Ther"},{"key":"2026090818353387800_vkag238-B16","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1016\/j.jcmgh.2017.12.003","article-title":"Estrogen receptor alpha loss-of-function protects female mice from DSS-induced experimental colitis","volume":"5","author":"Goodman","year":"2018","journal-title":"Cell Mol Gastroenterol Hepatol"},{"key":"2026090818353387800_vkag238-B17","doi-asserted-by":"publisher","first-page":"1255","DOI":"10.1038\/mi.2014.15","article-title":"Loss of estrogen-mediated immunoprotection underlies female gender bias in experimental Crohn\u2019s-like ileitis","volume":"7","author":"Goodman","year":"2014","journal-title":"Mucosal Immunol"},{"key":"2026090818353387800_vkag238-B18","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1084\/jem.179.2.589","article-title":"Regulatory interactions between CD45RBhigh and CD45RBlow CD4+ T cells are important for the balance between protective and pathogenic cell-mediated immunity","volume":"179","author":"Powrie","year":"1994","journal-title":"J Exp Med"},{"key":"2026090818353387800_vkag238-B19","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.cellimm.2015.01.018","article-title":"Estrogen receptors regulate innate immune cells and signaling pathways","volume":"294","author":"Kovats","year":"2015","journal-title":"Cell Immunol"},{"key":"2026090818353387800_vkag238-B20","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1002\/immu.200310027","article-title":"Estradiol enhances primary antigen-specific CD4 T cell responses and Th1 development in vivo. Essential role of estrogen receptor alpha expression in hematopoietic cells","volume":"33","author":"Maret","year":"2003","journal-title":"Eur J Immunol"},{"key":"2026090818353387800_vkag238-B21","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/s40364-020-00223-2","article-title":"The role of estrogen receptor beta in breast cancer","volume":"8","author":"Zhou","year":"2020","journal-title":"Biomark Res"},{"key":"2026090818353387800_vkag238-B22","doi-asserted-by":"publisher","first-page":"eabo7975","DOI":"10.1126\/sciimmunol.abo7975","article-title":"Aire drives steroid hormone biosynthesis by medullary thymic epithelial cells","volume":"8","author":"Taves","year":"2023","journal-title":"Sci Immunol"},{"key":"2026090818353387800_vkag238-B23","doi-asserted-by":"publisher","first-page":"1161901","DOI":"10.3389\/fimmu.2023.1161901","article-title":"The chromatin and single-cell transcriptional landscapes of CD4 T cells in inflammatory bowel disease link risk loci with a proinflammatory Th17 cell population","volume":"14","author":"Medina","year":"2023","journal-title":"Front Immunol"},{"key":"2026090818353387800_vkag238-B24","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1186\/s40164-018-0116-7","article-title":"Mechanisms for estrogen receptor expression in human cancer","volume":"7","author":"Hua","year":"2018","journal-title":"Exp Hematol Oncol"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/215\/9\/vkag238\/70999897\/vkag238.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/215\/9\/vkag238\/70999897\/vkag238.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T22:35:39Z","timestamp":1788906939000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/doi\/10.1093\/jimmun\/vkag238\/8788389"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,29]]},"references-count":24,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,8,29]]}},"URL":"https:\/\/doi.org\/10.1093\/jimmun\/vkag238","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,9]]},"published":{"date-parts":[[2026,8,29]]},"article-number":"vkag238"}}