{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T10:25:11Z","timestamp":1788431111064,"version":"build-2803163510"},"reference-count":28,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2020,11,4]],"date-time":"2020-11-04T00:00:00Z","timestamp":1604448000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Stiftung Experimentelle Biomedizin"},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["314730-146204"],"award-info":[{"award-number":["314730-146204"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["314730_166381\/1,"],"award-info":[{"award-number":["314730_166381\/1,"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["314730_166381\/2"],"award-info":[{"award-number":["314730_166381\/2"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"name":"International Organisation for Studies in IBD"},{"DOI":"10.13039\/100018353","name":"European Crohn\u2019s and Colitis Organisation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100018353","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,3,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Fistulas represent a frequent and severe complication in patients with Crohn disease (CD). Tumor necrosis factor-alpha (TNF-\u03b1), transforming growth factor-beta, and interleukin (IL)-13 are known to trigger epithelial-mesenchymal transition (EMT), promoting fistula formation. Here, we investigated the role of T-lymphocytes (T cells) in fistula pathogenesis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>CD3+CD8-, CD3+CD8+, or CD45+CD3- cells from healthy volunteers, patients with CD, and patients with CD with perianal fistula were co-cultured with HT-29 cells. The EMT, cytokine production, and mRNA expression were analyzed. Perianal CD fistula specimens were immunohistochemically stained for cytokines and their receptors. The effect of cytokines on EMT induction was investigated using an EMT spheroid model.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Patients with CD with fistula revealed more CD3+CD8- and less CD3+CD8+ T cells in blood than healthy control patients and patients with CD without fistula. In perianal fistula specimens, CD4+ cells\u2014and to a lesser extent CD8+ cells\u2014were highly present around fistula tracts. When co-cultured with HT-29 cells, both cell subsets promoted EMT-related gene expression and TNF-\u03b1 production in a time-dependent manner. The CD3+CD8- T cells from patients with CD with fistula also produced higher amounts of IL-13 than cells from healthy control patients or patients with CD without a fistula. We found that IL-22 and IL-22R\u03b11 were highly expressed in perianal CD fistula specimens and that IL-22 cotreatment potentiated TNF-\u03b1-induced EMT in HT-29 spheroids.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Our data indicate that both CD3+CD8- and CD3+CD8+ T cells play an important role in the pathogenesis of perianal CD fistulas by the secretion of TNF-\u03b1. Our data support clinical evidence indicating that anti-TNF-\u03b1 therapy is effective in fistula treatment and identify IL-13 and IL-22 as possible novel therapeutic targets for fistula therapy.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/ibd\/izaa240","type":"journal-article","created":{"date-parts":[[2020,11,4]],"date-time":"2020-11-04T11:32:19Z","timestamp":1604489539000},"page":"538-549","source":"Crossref","is-referenced-by-count":21,"title":["Contribution of CD3+CD8- and CD3+CD8+ T Cells to TNF-<i>\u03b1<\/i> Overexpression in Crohn Disease\u2013Associated Perianal Fistulas and Induction of Epithelial-Mesenchymal Transition in HT-29 Cells"],"prefix":"10.1093","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5438-3279","authenticated-orcid":false,"given":"Ramona S","family":"Bruckner","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich , Zurich, Switzerland"},{"name":"Department of Gastroenterology and Hepatology, Leiden University Medical Center , Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne R","family":"Spalinger","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich , Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marieke C","family":"Barnhoorn","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Leiden University Medical Center , Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Feakins","sequence":"additional","affiliation":[{"name":"Department of Histopathology, Royal Free Hospital , London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alois","family":"Fuerst","sequence":"additional","affiliation":[{"name":"Department of Surgery, Caritas-Krankenhaus St. Josef , Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekkehard C","family":"Jehle","sequence":"additional","affiliation":[{"name":"Department of Surgery, Oberschwaben-Klinik , Ravensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Rickenbacher","sequence":"additional","affiliation":[{"name":"Department of Surgery, University Hospital Zurich, University of Zurich , Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Turina","sequence":"additional","affiliation":[{"name":"Department of Surgery, University Hospital Zurich, University of Zurich , Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Niechcial","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich , Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Lang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich , Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas J A C","family":"Hawinkels","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Leiden University Medical Center , Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea E","family":"van der Meulen-de Jong","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Leiden University Medical Center , Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hein W","family":"Verspaget","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Leiden University Medical Center , Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerhard","family":"Rogler","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich , Zurich, Switzerland"},{"name":"Zurich Center for Integrative Human Physiology, University of Zurich , Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Scharl","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich , Zurich, Switzerland"},{"name":"Zurich Center for Integrative Human Physiology, University of Zurich , Zurich, 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