{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T06:36:06Z","timestamp":1790922966424,"version":"4.1.0"},"reference-count":30,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2017,10,3]],"date-time":"2017-10-03T00:00:00Z","timestamp":1506988800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2017,10,3]],"date-time":"2017-10-03T00:00:00Z","timestamp":1506988800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2017,11]]},"abstract":"<jats:p>Imbalance between T regulatory (Treg) and T effector (Teff) cells is likely to contribute to the induction and perpetuation of liver damage in autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (AISC) either through inability of Tregs to restrain proliferation and effector cytokine production by responders or through conversion of Tregs into T helper type 1 (Th1) or type 17 (Th17) effector lymphocytes. We investigated the effect of Treg skewing on the phenotypic and functional properties of CD4<jats:sup>+<\/jats:sup>CD127<jats:sup>+<\/jats:sup>CD25<jats:sup>high<\/jats:sup> cells, an activated subset of Teff, in 32 patients with AIH and 20 with AISC and in 36 healthy subjects. In AIH\/AISC we noted a substantial increase in peripheral blood\u2013derived CD4<jats:sup>+<\/jats:sup>CD127<jats:sup>+<\/jats:sup> CD25<jats:sup>high<\/jats:sup> cells that display a Th1\/Th17 phenotypic profile, as reflected by heightened interferon gamma and interleukin 17 (IL\u201017) production as well as by high levels of T\u2010bet and related orphan receptor 3 expression, which is strongly correlated with disease activity. CD4<jats:sup>+<\/jats:sup>CD127<jats:sup>+<\/jats:sup>CD25<jats:sup>high<\/jats:sup> cells are unresponsive to low\u2010dose IL\u20102 and in patients have marked proliferative ability, further enhanced by stimulation with IL\u20107. CD4<jats:sup>+<\/jats:sup>CD127<jats:sup>+<\/jats:sup>CD25<jats:sup>high<\/jats:sup> cells obtained from CD4<jats:sup>+<\/jats:sup> cells exposed to Treg polarizing conditions display enhanced IL\u201010 production; up\u2010regulate CD49b and LAG\u20103, markers of T regulatory 1 cells; and effectively suppress responder cell proliferation in both healthy subjects and AIH\/AISC patients through a mechanism which is dependent on interferon gamma and IL\u201017. The suppressive function of CD4<jats:sup>+<\/jats:sup>CD127<jats:sup>+<\/jats:sup>CD25<jats:sup>high<\/jats:sup> cells is maintained upon proinflammatory challenge in healthy subjects but not in AIH\/AISC. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: Treg skewing confers activated Teff phenotypic and functional properties of T regulatory 1 cells in health and in AIH\/AISC, though suppressive function is lost in patients upon proinflammatory challenge; protracted modulation of the inflammatory environment is required to attenuate the effector potential while boosting immunoregulatory properties in Teff. (H<jats:sc>epatology<\/jats:sc> 2017;66:1570\u20131584).<\/jats:p>","DOI":"10.1002\/hep.29307","type":"journal-article","created":{"date-parts":[[2017,6,9]],"date-time":"2017-06-09T12:36:41Z","timestamp":1497011801000},"page":"1570-1584","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":42,"title":["Regulatory T\u2010cell conditioning endows activated effector T cells with suppressor function in autoimmune hepatitis\/autoimmune sclerosing cholangitis"],"prefix":"10.1097","volume":"66","author":[{"given":"Rodrigo","family":"Liberal","sequence":"first","affiliation":[{"name":"Department of Liver Studies, Division of Transplantation Immunology & Mucosal Biology, MRC Centre for Transplantation, Faculty of Life Sciences & Medicine,King's College London,London,UK"},{"name":"Gastroenterology Department, Centro Hospitalar S\u00e3o Jo\u00e3o,Faculty of Medicine of the University of Porto,Porto,Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte R.","family":"Grant","sequence":"additional","affiliation":[{"name":"Department of Liver Studies, Division of Transplantation Immunology & Mucosal Biology, MRC Centre for Transplantation, Faculty of Life Sciences & Medicine,King's College London,London,UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammed","family":"Yuksel","sequence":"additional","affiliation":[{"name":"Department of Liver Studies, Division of Transplantation Immunology & Mucosal Biology, MRC Centre for Transplantation, Faculty of Life Sciences & Medicine,King's College London,London,UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathon","family":"Graham","sequence":"additional","affiliation":[{"name":"Department of Liver Studies, Division of Transplantation Immunology & Mucosal Biology, MRC Centre for Transplantation, Faculty of Life Sciences & Medicine,King's College London,London,UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alireza","family":"Kalbasi","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Beth Israel Deaconess Medical Center,Harvard Medical School,Boston,MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Liver Studies, Division of Transplantation Immunology & Mucosal Biology, MRC Centre for Transplantation, Faculty of Life Sciences & Medicine,King's College London,London,UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Heneghan","sequence":"additional","affiliation":[{"name":"Department of Liver Studies, Division of Transplantation Immunology & Mucosal Biology, MRC Centre for Transplantation, Faculty of Life Sciences & Medicine,King's College London,London,UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgina","family":"Mieli\u2010Vergani","sequence":"additional","affiliation":[{"name":"Department of Liver Studies, Division of Transplantation Immunology & Mucosal Biology, MRC Centre for Transplantation, Faculty of Life Sciences & Medicine,King's College London,London,UK"},{"name":"MowatLabs Paediatric Liver, GI & Nutrition Centre, Faculty of Life Sciences & Medicine,King's College London,London,UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Vergani","sequence":"additional","affiliation":[{"name":"Department of Liver Studies, Division of Transplantation Immunology & Mucosal Biology, MRC Centre for Transplantation, Faculty of Life Sciences & Medicine,King's College London,London,UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Serena","family":"Longhi","sequence":"additional","affiliation":[{"name":"Department of Liver Studies, Division of Transplantation Immunology & Mucosal Biology, MRC Centre for Transplantation, Faculty of Life Sciences & Medicine,King's College London,London,UK"},{"name":"Division of Gastroenterology, Beth Israel Deaconess Medical Center,Harvard Medical School,Boston,MA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2017,10,3]]},"reference":[{"key":"hep29307-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1038\/nrgastro.2011.69","article-title":"Autoimmune hepatitis","volume":"8","year":"2011","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"hep29307-bib-0002-20241017","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1053\/jhep.2001.22131","article-title":"Autoimmune hepatitis\/sclerosing cholangitis overlap syndrome in childhood: a 16\u2010year prospective 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