{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T02:57:25Z","timestamp":1790996245024,"version":"4.1.0"},"reference-count":32,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T00:00:00Z","timestamp":1709251200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Eur J Immunol"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Tolerance to self\u2010proteins involves multiple mechanisms, including conventional CD4\n                    <jats:sup>+<\/jats:sup>\n                    T\u2010cell (Tconv) deletion in the thymus and the recruitment of natural regulatory T cells (nTregs). The significant incidence of autoantibodies specific for the blood coagulation factor VIII (FVIII) in healthy donors illustrates that tolerance to self\u2010proteins is not always complete. In contrast to FVIII\u2010specific Tconvs, FVIII\u2010specific nTregs have never been revealed and characterized. To determine the frequency of FVIII\u2010specific Tregs in human peripheral blood, we assessed the specificity of in vitro expanded Tregs by the membrane expression of the CD137 activation marker. Amplified Tregs maintain high levels of FOXP3 expression and exhibit almost complete demethylation of the\n                    <jats:italic>FOXP3<\/jats:italic>\n                    Treg\u2010specific demethylated region. The cells retained FOXP3 expression after long\u2010term culture in vitro, strongly suggesting that FVIII\u2010specific Tregs are derived from the thymus. From eleven healthy donors, we estimated the frequencies of FVIII\u2010specific Tregs at 0.17 cells per million, which is about 10\u2010fold lower than the frequency of FVIII\u2010specific CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells we previously published. Our results shed light on the mechanisms of FVIII tolerance by a renewed approach that could be extended to other self\u2010 or non\u2010self\u2010antigens.\n                  <\/jats:p>","DOI":"10.1002\/eji.202350506","type":"journal-article","created":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T22:44:58Z","timestamp":1709333098000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Frequency of natural regulatory T cells specific for factor VIII in the peripheral blood of healthy donors"],"prefix":"10.1002","volume":"54","author":[{"given":"Catherine","family":"Menier","sequence":"first","affiliation":[{"name":"CEA INRAE D\u00e9partement M\u00e9dicaments et Technologies pour la Sant\u00e9 SIMoS Universit\u00e9 de Paris\u2010Saclay  Gif\u2010sur\u2010Yvette France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvain","family":"Meunier","sequence":"additional","affiliation":[{"name":"CEA 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