{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T03:37:48Z","timestamp":1790048268879,"version":"4.0.1"},"reference-count":17,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2015,12,23]],"date-time":"2015-12-23T00:00:00Z","timestamp":1450828800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"European Union Seventh Framework Programme (Project EUtrain)","award":["FP7-PEOPLE-2011-ITN"],"award-info":[{"award-number":["FP7-PEOPLE-2011-ITN"]}]},{"name":"European Union Seventh Framework Programme (Marie Curie Action: Initial Training Networks)","award":["FP7-PEOPLE-2011-ITN"],"award-info":[{"award-number":["FP7-PEOPLE-2011-ITN"]}]},{"name":"European Union Seventh Framework Programme (Marie Curie Action: Initial Training Networks)","award":["289903"],"award-info":[{"award-number":["289903"]}]},{"name":"Vidi grant from The Netherlands Organization for Scientific Research"},{"name":"Dutch Arthritis Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2016,1]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Resistance of Teff cells to Treg cell\u2013mediated suppression contributes to the breakdown of peripheral tolerance in the inflamed joints of patients with juvenile idiopathic arthritis (JIA). However, unanswered questions are whether this resistant phenotype is self\u2010sustained and whether CD8+ and CD4+ Teff cells share the same mechanism of resistance to suppression. We undertook this study to investigate intrinsic resistance of CD8+ Teff cells to suppression and to determine how this can be targeted therapeutically.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>CD8+ or CD4+ Teff cells were cultured with or without antigen\u2010presenting cells (APCs) in Treg cell\u2013dependent and \u2013independent suppression assays. Synovial fluid (SF)\u2013derived Teff cells were crosscultured with peripheral blood (PB) Treg cells from JIA patients or healthy controls. Tumor necrosis factor (TNF) or interferon\u2010\u03b3 (IFN\u03b3) blocking agents were used to restore Teff cell responsiveness to suppression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Suppression of cell proliferation and cytokine production in CD8+ Teff cells from the SF of JIA patients was severely impaired compared to that in CD8+ Teff cells from the PB of JIA patients, regardless of the presence of APCs and CD4+ Teff cells. Similar to CD4+ Teff cells, impaired suppression of CD8+ Teff cells was shown to be an intrinsic feature of this cell population. While TNF blockade restored both CD8+ and CD4+ Teff cell susceptibility to suppression, autocrine release of IFN\u03b3 selectively sustained CD8+ Teff cell resistance, which could be relieved by IFN\u03b3 blockade.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Unlike CD4+ Teff cells, resistance of CD8+ Teff cells to suppression at the site of autoimmune inflammation is maintained by autocrine release of IFN\u03b3, and blockade of IFN\u03b3 restores CD8+ Teff cell responsiveness to suppression. These findings indicate a potential therapeutic value of blocking IFN\u03b3 to restore immune regulation in JIA.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.39418","type":"journal-article","created":{"date-parts":[[2015,9,11]],"date-time":"2015-09-11T12:53:03Z","timestamp":1441975983000},"page":"229-236","source":"Crossref","is-referenced-by-count":30,"title":["Self\u2010Sustained Resistance to Suppression of CD8+ Teff Cells at the Site of Autoimmune Inflammation Can Be Reversed by Tumor Necrosis Factor and Interferon\u2010\u03b3 Blockade"],"prefix":"10.1002","volume":"68","author":[{"given":"Alessandra","family":"Petrelli","sequence":"first","affiliation":[{"name":"University Medical Center Utrecht Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen J.","family":"Wehrens","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rianne C.","family":"Scholman","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berent J.","family":"Prakken","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian J.","family":"Vastert","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Femke","family":"van Wijk","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,12,23]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2012.05.021"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2012.149"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.10.5967"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03725"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2009.09.011"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-12-328187"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.38132"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.30503"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201041004"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-012-9674-3"},{"key":"e_1_2_7_12_1","first-page":"363","article-title":"CD8+ T cell profiles in patients with rheumatoid arthritis and their relationship to disease activity. 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