PMID- 33146394 OWN - NLM STAT- MEDLINE DCOM- 20220207 LR - 20220207 IS - 1536-4844 (Electronic) IS - 1078-0998 (Linking) VI - 27 IP - 4 DP - 2021 Mar 15 TI - Contribution of CD3+CD8- and CD3+CD8+ T Cells to TNF-alpha Overexpression in Crohn Disease-Associated Perianal Fistulas and Induction of Epithelial-Mesenchymal Transition in HT-29 Cells. PG - 538-549 LID - 10.1093/ibd/izaa240 [doi] AB - BACKGROUND: Fistulas represent a frequent and severe complication in patients with Crohn disease (CD). Tumor necrosis factor-alpha (TNF-alpha), 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. METHODS: 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. RESULTS: 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-and to a lesser extent CD8+ cells-were highly present around fistula tracts. When co-cultured with HT-29 cells, both cell subsets promoted EMT-related gene expression and TNF-alpha 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-22Ralpha1 were highly expressed in perianal CD fistula specimens and that IL-22 cotreatment potentiated TNF-alpha-induced EMT in HT-29 spheroids. CONCLUSIONS: 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-alpha. Our data support clinical evidence indicating that anti-TNF-alpha therapy is effective in fistula treatment and identify IL-13 and IL-22 as possible novel therapeutic targets for fistula therapy. CI - (c) 2020 Crohn's & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. FAU - Bruckner, Ramona S AU - Bruckner RS AD - Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. AD - Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands. FAU - Spalinger, Marianne R AU - Spalinger MR AD - Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. FAU - Barnhoorn, Marieke C AU - Barnhoorn MC AD - Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands. FAU - Feakins, Roger AU - Feakins R AD - Department of Histopathology, Royal Free Hospital, London, United Kingdom. FAU - Fuerst, Alois AU - Fuerst A AD - Department of Surgery, Caritas-Krankenhaus St. Josef, Regensburg, Germany. FAU - Jehle, Ekkehard C AU - Jehle EC AD - Department of Surgery, Oberschwaben-Klinik, Ravensburg, Germany. FAU - Rickenbacher, Andreas AU - Rickenbacher A AD - Department of Surgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland. FAU - Turina, Matthias AU - Turina M AD - Department of Surgery, University Hospital Zurich, University of Zurich, Zurich, Switzerland. FAU - Niechcial, Anna AU - Niechcial A AD - Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. FAU - Lang, Silvia AU - Lang S AD - Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. FAU - Hawinkels, Lukas J A C AU - Hawinkels LJAC AD - Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands. FAU - van der Meulen-de Jong, Andrea E AU - van der Meulen-de Jong AE AD - Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands. FAU - Verspaget, Hein W AU - Verspaget HW AD - Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands. FAU - Rogler, Gerhard AU - Rogler G AD - Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. AD - Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland. FAU - Scharl, Michael AU - Scharl M AD - Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. AD - Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - Inflamm Bowel Dis JT - Inflammatory bowel diseases JID - 9508162 RN - 0 (Cytokines) RN - 0 (Interleukin-13) RN - 0 (Tumor Necrosis Factor-alpha) SB - IM MH - CD8-Positive T-Lymphocytes/*immunology MH - *Crohn Disease/immunology MH - Cytokines/metabolism MH - *Epithelial-Mesenchymal Transition MH - HT29 Cells MH - Humans MH - Interleukin-13/metabolism MH - *Rectal Fistula/etiology MH - Tumor Necrosis Factor-alpha/*metabolism OTO - NOTNLM OT - Crohn disease OT - T-lymphocytes OT - fistulas OT - tumor necrosis factor-alpha EDAT- 2020/11/05 06:00 MHDA- 2022/02/08 06:00 CRDT- 2020/11/04 08:44 PHST- 2020/03/19 00:00 [received] PHST- 2020/11/05 06:00 [pubmed] PHST- 2022/02/08 06:00 [medline] PHST- 2020/11/04 08:44 [entrez] AID - 5955654 [pii] AID - 10.1093/ibd/izaa240 [doi] PST - ppublish SO - Inflamm Bowel Dis. 2021 Mar 15;27(4):538-549. doi: 10.1093/ibd/izaa240.