Contribution of CD3+CD8- and CD3+CD8+ T Cells to TNF-α Overexpression in Crohn Disease-Associated Perianal Fistulas and Induction of Epithelial-Mesenchymal Transition in HT-29 Cells.

Abstract

BACKGROUND:

Fistulas represent a frequent and severe complication in patients with Crohn disease (CD). Tumor necrosis factor-alpha (TNF-α), 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-α 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-22Rα1 were highly expressed in perianal CD fistula specimens and that IL-22 cotreatment potentiated TNF-α-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-α. Our data support clinical evidence indicating that anti-TNF-α therapy is effective in fistula treatment and identify IL-13 and IL-22 as possible novel therapeutic targets for fistula therapy.

• Authors: Ramona S Bruckner, Marianne R Spalinger, Marieke C Barnhoorn, Roger Feakins, Alois Fuerst, Ekkehard C Jehle, Andreas Rickenbacher, Matthias Turina, Anna Niechcial, Silvia Lang, Lukas J A C Hawinkels, Andrea E van der Meulen-de Jong, Hein W Verspaget, Gerhard Rogler, Michael Scharl
• Journal: Inflammatory bowel diseases (Inflamm Bowel Dis) Vol. 27 Issue 4 Pg. 538-549 (03 15 2021) ISSN: 1536-4844 [Electronic] England
• PMID: 33146394 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Cytokines
• Interleukin-13
• Tumor Necrosis Factor-alpha

Topics

• CD8-Positive T-Lymphocytes (immunology)
• Crohn Disease (immunology)
• Cytokines (metabolism)
• Epithelial-Mesenchymal Transition
• HT29 Cells
• Humans
• Interleukin-13 (metabolism)
• Rectal Fistula (etiology)
• Tumor Necrosis Factor-alpha (metabolism)