The FOXP3 + Pro-Inflammatory T Cell: A Potential Therapeutic Target in Crohn's Disease.

Autor:	Kosinsky RL; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; Robert Bosch Center for Tumor Diseases, Stuttgart, Germany., Gonzalez MM; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota., Saul D; Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota; Department of Trauma and Reconstructive Surgery, Eberhard Karls University Tübingen, BG Trauma Center, Tübingen, Germany., Barros LL; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil., Sagstetter MR; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota., Fedyshyn Y; Department of Physiology, Mayo Clinic, Rochester, Minnesota., Nair A; Division of Computational Biology, Mayo Clinic, Rochester, Minnesota., Sun Z; Division of Computational Biology, Mayo Clinic, Rochester, Minnesota., Hamdan FH; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota., Gibbons HR; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota., Perez Pachon ME; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota., Druliner BR; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota., Johnsen SA; Robert Bosch Center for Tumor Diseases, Stuttgart, Germany., Faubion WA; Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona. Electronic address: Faubion.william@mayo.edu.
Jazyk:	angličtina
Zdroj:	Gastroenterology [Gastroenterology] 2024 Apr; Vol. 166 (4), pp. 631-644.e17. Date of Electronic Publication: 2024 Jan 09.
DOI:	10.1053/j.gastro.2024.01.007
Abstrakt:	Background & Aims: The incidence of Crohn's disease (CD) continues to increase worldwide. The contribution of CD4 + cell populations remains to be elucidated. We aimed to provide an in-depth transcriptional assessment of CD4 + T cells driving chronic inflammation in CD. Methods: We performed single-cell RNA-sequencing in CD4 + T cells isolated from ileal biopsies of patients with CD compared with healthy individuals. Cells underwent clustering analysis, followed by analysis of gene signaling networks. We overlapped our differentially expressed genes with publicly available microarray data sets and performed functional in vitro studies, including an in vitro suppression assay and organoid systems, to model gene expression changes observed in CD regulatory T (Treg) cells and to test predicted therapeutics. Results: We identified 5 distinct FOXP3 + regulatory Treg subpopulations. Tregs isolated from healthy controls represent the origin of pseudotemporal development into inflammation-associated subtypes. These proinflammatory Tregs displayed a unique responsiveness to tumor necrosis factor-α signaling with impaired suppressive activity in vitro and an elevated cytokine response in an organoid coculture system. As predicted in silico, the histone deacetylase inhibitor vorinostat normalized gene expression patterns, rescuing the suppressive function of FOXP3 + cells in vitro. Conclusions: We identified a novel, proinflammatory FOXP3 + T cell subpopulation in patients with CD and developed a pipeline to specifically target these cells using the US Food and Drug Administration-approved drug vorinostat. (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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