{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T22:49:13Z","timestamp":1791067753697,"version":"4.1.0"},"reference-count":44,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2014,8,26]],"date-time":"2014-08-26T00:00:00Z","timestamp":1409011200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"The Kennedy Trust for Rheumatology Research"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2014,9]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Functionally impaired Treg cells expressing abnormally low levels of CTLA\u20104 have been well documented in rheumatoid arthritis (RA). However, the molecular defect underlying this reduced expression is unknown. The aims of this study were to assess the role of DNA methylation in regulating CTLA\u20104 expression in Treg cells isolated from RA patients and to elucidate the mechanism of their reduced suppressor function.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>CTLA\u20104 expression in Treg cells from RA patients and healthy controls was measured by quantitative polymerase chain reaction (PCR) and flow cytometry. Methylation of the CTLA\u20104 gene promoter was analyzed by bisulfite\u2010specific PCR, followed by sequencing. Methylation\u2010dependent transcriptional activity of the CTLA\u20104 gene promoter was measured by luciferase assay, and NF\u2010AT binding to the CTLA\u20104 gene promoter was determined by chromatin immunoprecipitation. The role of CTLA\u20104 expression in controlling Teff cells was analyzed using an autologous mixed lymphocyte reaction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Down\u2010regulation of CTLA\u20104 expression in Treg cells from RA patients was caused by methylation of a previously unidentified NF\u2010AT binding site within the CTLA\u20104 gene promoter. As a consequence, Treg cells were unable to induce expression and activation of the tryptophan\u2010degrading enzyme indoleamine 2,3\u2010dioxygenase (IDO), which in turn resulted in a failure to activate the immunomodulatory kynurenine pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>We show for the first time that epigenetic modifications contribute to defective Treg cell function in RA through an inability to activate the IDO pathway. Therefore, this study sets a precedent for investigating potential therapeutic strategies aimed at reinforcing the IDO pathway in RA patients.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.38715","type":"journal-article","created":{"date-parts":[[2014,5,28]],"date-time":"2014-05-28T16:35:13Z","timestamp":1401294913000},"page":"2344-2354","source":"Crossref","is-referenced-by-count":137,"title":["Treg Cell Function in Rheumatoid Arthritis Is Compromised by CTLA\u20104 Promoter Methylation Resulting in a Failure to Activate the Indoleamine 2,3\u2010Dioxygenase Pathway"],"prefix":"10.1002","volume":"66","author":[{"given":"Adam P.","family":"Cribbs","sequence":"first","affiliation":[{"name":"Kennedy Institute and University of Oxford Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Kennedy","sequence":"additional","affiliation":[{"name":"Kennedy Institute and University of Oxford Oxford 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