Wnt–β-catenin activation epigenetically reprograms Treg cells in inflammatory bowel disease and dysplastic progression

Jasmin Quandt, Stephen Arnovitz, Leila Haghi, Janine Woehlk, Azam Mohsin, Michael Okoreeh, Priya S. Mathur, Akinola Olumide Emmanuel, Abu Osman, Manisha Krishnan, Samuel B. Morin, Alexander T. Pearson, Randy F. Sweis, Joel Pekow, Christopher R. Weber, Khashayarsha Khazaie, Fotini Gounari

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

The diversity of regulatory T (Treg) cells in health and in disease remains unclear. Individuals with colorectal cancer harbor a subpopulation of RORγt+ Treg cells with elevated expression of β-catenin and pro-inflammatory properties. Here we show progressive expansion of RORγt+ Treg cells in individuals with inflammatory bowel disease during inflammation and early dysplasia. Activating Wnt–β-catenin signaling in human and murine Treg cells was sufficient to recapitulate the disease-associated increase in the frequency of RORγt+ Treg cells coexpressing multiple pro-inflammatory cytokines. 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 Treg cells. Activation of β-catenin signaling interferes with this function and promotes the disease-associated RORγt+ Treg phenotype.

Original languageEnglish (US)
Pages (from-to)471-484
Number of pages14
JournalNature immunology
Volume22
Issue number4
DOIs
StatePublished - Apr 2021

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint

Dive into the research topics of 'Wnt–β-catenin activation epigenetically reprograms T<sub>reg</sub> cells in inflammatory bowel disease and dysplastic progression'. Together they form a unique fingerprint.

Cite this