{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T10:07:08Z","timestamp":1791281228126,"version":"4.1.0"},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T00:00:00Z","timestamp":1741305600000},"content-version":"vor","delay-in-days":3840,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,9,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The maintenance of FOXP3 expression in CD25hi regulatory T cells (Tregs) is crucial to the control of inflammation and essential for successful Treg transfer therapies. Coexpression of CD25 and FOXP3 in combination with a hypomethylated region within the FOXP3 gene, called the Treg-specific demethylated region (TSDR), is considered the hallmark of stable Tregs. The TSDR is an epigenetic motif that is important for stable FOXP3 expression and is used as a biomarker to measure Treg lineage commitment. In this study, we report that, unlike in peripheral blood, CD4+ T cell expression of CD25 and FOXP3 is frequently dissociated at the inflamed site in patients with juvenile idiopathic arthritis, which led us to question the stability of human Tregs in chronic inflammatory environments. We describe a novel CD4+CD127loCD25hi human T cell population that exhibits extensive TSDR and promoter demethylation in the absence of stable FOXP3 expression. This population expresses high levels of CTLA-4 and can suppress T conventional cell proliferation in vitro. These data collectively suggest that this population may represent a chronically activated FOXP3lo Treg population. We show that these cells have defects in IL-2 signaling and reduced expression of a deubiquitinase important for FOXP3 stability. Clinically, the proportions of these cells within the CD25hi T cell subset are increased in patients with the more severe courses of disease. Our study demonstrates, therefore, that hypomethylation at the TSDR can be decoupled from FOXP3 expression in human T cells and that environment-specific breakdown in FOXP3 stability may compromise the resolution of inflammation in juvenile idiopathic arthritis.<\/jats:p>","DOI":"10.4049\/jimmunol.1400599","type":"journal-article","created":{"date-parts":[[2014,8,5]],"date-time":"2014-08-05T06:18:09Z","timestamp":1407219489000},"page":"2699-2708","source":"Crossref","is-referenced-by-count":60,"title":["Hypomethylation at the Regulatory T Cell\u2013Specific Demethylated Region in CD25hi T Cells Is Decoupled from FOXP3 Expression at the Inflamed Site in Childhood Arthritis"],"prefix":"10.1093","volume":"193","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0071-1163","authenticated-orcid":false,"given":"David","family":"Bending","sequence":"first","affiliation":[{"name":"Infection, Inflammation and Rheumatology Section, University College London Institute of Child Health , London WC1N 1EH ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne M","family":"Pesenacker","sequence":"additional","affiliation":[{"name":"Infection, Inflammation and Rheumatology Section, University College London Institute of Child Health , London WC1N 1EH ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Ursu","sequence":"additional","affiliation":[{"name":"Infection, Inflammation and Rheumatology Section, University College London Institute of Child Health , London WC1N 1EH ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiong","family":"Wu","sequence":"additional","affiliation":[{"name":"Medical School, Imperial College London , London SW7 2AZ ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Lom","sequence":"additional","affiliation":[{"name":"Infection, Inflammation and Rheumatology Section, University College London Institute of Child Health , London WC1N 1EH ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Balathas","family":"Thirugnanabalan","sequence":"additional","affiliation":[{"name":"Infection, Inflammation and Rheumatology Section, University College London Institute of Child Health , London WC1N 1EH ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy R","family":"Wedderburn","sequence":"additional","affiliation":[{"name":"Infection, Inflammation and Rheumatology Section, University College London Institute of Child Health , London WC1N 1EH ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,9,15]]},"reference":[{"key":"2025030707353621000_r1","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1126\/science.1079490","article-title":"Control of regulatory T cell development by the transcription factor Foxp3","volume":"299","author":"Hori","year":"2003","journal-title":"Science"},{"key":"2025030707353621000_r2","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.4049\/jimmunol.155.3.1151","article-title":"Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases","volume":"155","author":"Sakaguchi","year":"1995","journal-title":"J. Immunol."},{"key":"2025030707353621000_r3","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/ni904","article-title":"Foxp3 programs the development and function of CD4+CD25+ regulatory T cells","volume":"4","author":"Fontenot","year":"2003","journal-title":"Nat. Immunol."},{"key":"2025030707353621000_r4","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/ni909","article-title":"An essential role for Scurfin in CD4+CD25+ T regulatory cells","volume":"4","author":"Khattri","year":"2003","journal-title":"Nat. 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