Details

Autor(en) / Beteiligte

• Kosinsky, Robyn Laura
• Gonzalez, Michelle M.
• Saul, Dominik
• Barros, Luísa Leite
• Sagstetter, Mary R.
• Fedyshyn, Yaroslav
• Nair, Asha
• Sun, Zhifu
• Hamdan, Feda H.
• Gibbons, Hunter R.
• Perez Pachon, Mauricio E.
• Druliner, Brooke R.
• Johnsen, Steven A.
• Faubion, William A.

Titel

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

Ist Teil von

• Gastroenterology (New York, N.Y. 1943), 2024-04, Vol.166 (4), p.631-644.e17

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2024

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. 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. 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. 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. Crohn’s intestinal lesions are enriched in a unique population of FOXP3+ cells that exhibit a pro-inflammatory transcriptional signature consistent with strong tumor necrosis factor–α signaling.