Citations 1
Wnt/β-catenin activation epigenetically reprograms Regulatory T cells in IBD and progression to dysplasia.
Gounari, Fotini , Quandt, Jasmin , Arnovitz, Stephen , Haghi, Leila, Woehlk, Janine, Moshin, Azam, Emmanuel, Akinola Olumide , Osman, Abu , Krishnan, Manisha, Morin, Samuel B., Weber, Christopher, Khazaie, Khashayarsha , Gounari, Fotini , Mohsin, Azam , Okoreeh, Michael K. , Mathur, Priya, Pearson, Alexander T. , Sweis, Randy F. , Pekow, Joel
No container title available | December 1, 2020 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract The molecular and functional diversity of regulatory T-cells (Tregs) in health and in disease remains unclear. We previously described in colorectal cancer (CRC) patients a subpopulation of RORγt+ Tregs with elevated expression of β-catenin and pro-inflammatory properties. Here we observed progressive expansion of RORγt+ Tregs in inflammatory bowel disease (IBD) patients during inflammation and early dysplasia. Activating Wnt/β-catenin signaling in human and murine Tregs was sufficient to recapitulate the disease-associated increase in frequencies of RORγt+ Tregs expressing IL-17, IFN-γ, and TNFa. We found that binding of the β-catenin interacting partner, TCF-1, to DNA overlapped with Foxp3 binding at enhancer sites of pro-inflammatory pathway genes. Sustained Wnt/β-catenin activation induced newly accessible chromatin sites in these genes and upregulated their expression. These findings indicate that TCF-1 and Foxp3 together limit the expression of pro-inflammatory genes in Tregs. Activation of ꞵ-catenin signaling interferes with this function and promotes the disease-associated RORγt+ Treg phenotype.