{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T10:20:52Z","timestamp":1787912452009,"version":"build-2784847793"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T00:00:00Z","timestamp":1741305600000},"content-version":"vor","delay-in-days":3384,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,12,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Although there is great interest in harnessing the immunosuppressive potential of FOXP3+ regulatory T cells (Tregs) for treating autoimmunity, a sizeable knowledge gap exists regarding Treg fate in human disease. In juvenile idiopathic arthritis (JIA) patients, we have previously reported that atypical CD25+FOXP3\u2212 Treg-like cells uniquely populate the inflamed site. Intriguingly, their proportions relative to CD25+FOXP3+ Tregs associate with arthritis course, suggesting a role in disease. The ontogeny of these FOXP3\u2212 Treg-like cells is, however, unknown. In this study, we interrogated clonal relationships between CD4+ T cell subsets in JIA, using high-throughput TCR repertoire analysis. We reveal that FOXP3+ Tregs possess highly exclusive TCR\u03b2 usage from conventional T cells, in blood, and also at the inflamed site, where they are clonally expanded. Intriguingly, the repertoires of FOXP3+ Tregs in synovial fluid are highly overlapping with CD25+FOXP3\u2212 Treg-like cells, indicating fluctuations in FOXP3 expression in the inflamed joint. Furthermore, cultured synovial Tregs rapidly downregulated FOXP3 protein (but not mRNA), and this process was prevented by addition of synovial fluid from JIA patients, through an IL-6\u2013independent mechanism. Our findings suggest that most Tregs arise from a separate lineage from conventional T cells, and that this repertoire divergence is largely maintained under chronic inflammatory conditions. We propose that subsequent Treg expansions at the inflamed site creates an environment that leads to competition for limited resources within the synovium, resulting in the destabilization of FOXP3 expression in some Tregs.<\/jats:p>","DOI":"10.4049\/jimmunol.1500391","type":"journal-article","created":{"date-parts":[[2015,11,11]],"date-time":"2015-11-11T21:29:27Z","timestamp":1447277367000},"page":"5616-5624","source":"Crossref","is-referenced-by-count":27,"title":["Synovial Regulatory T Cells Occupy a Discrete TCR Niche in Human Arthritis and Require Local Signals To Stabilize FOXP3 Protein Expression"],"prefix":"10.1093","volume":"195","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, Institute of Child Health, University College London , London WC1N 1EH ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eirini","family":"Giannakopoulou","sequence":"additional","affiliation":[{"name":"Infection, Inflammation and Rheumatology Section, Institute of Child Health, University College London , London WC1N 1EH ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Lom","sequence":"additional","affiliation":[{"name":"Infection, Inflammation and Rheumatology Section, Institute of Child Health, University College London , 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, Institute of Child Health, University College London , London WC1N 1EH ,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,12,15]]},"reference":[{"key":"2025030704274702900_r1","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1097\/00002281-200307000-00010","article-title":"Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis","volume":"15","author":"Gambineri","year":"2003","journal-title":"Curr. Opin. Rheumatol."},{"key":"2025030704274702900_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":"2025030704274702900_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":"2025030704274702900_r4","doi-asserted-by":"crossref","first-page":"6435","DOI":"10.4049\/jimmunol.172.10.6435","article-title":"CD4+CD25bright regulatory T cells actively regulate inflammation in the joints of patients with the remitting form of juvenile idiopathic arthritis","volume":"172","author":"de Kleer","year":"2004","journal-title":"J. Immunol."},{"key":"2025030704274702900_r5","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1002\/art.23291","article-title":"Interleukin-17-producing T cells are enriched in the joints of children with arthritis, but have a reciprocal relationship to regulatory T cell numbers","volume":"58","author":"Nistala","year":"2008","journal-title":"Arthritis Rheum."},{"key":"2025030704274702900_r6","doi-asserted-by":"crossref","first-page":"2699","DOI":"10.4049\/jimmunol.1400599","article-title":"Hypomethylation at the regulatory T cell-specific demethylated region in CD25hi T cells is decoupled from FOXP3 expression at the inflamed site in childhood arthritis","volume":"193","author":"Bending","year":"2014","journal-title":"J. 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