Open AccessWnt–β-catenin activation epigenetically reprograms Treg cells in inflammatory bowel disease and dysplastic progression
Author(s) -
Jasmin Quandt,
Stephen Arnovitz,
Leila Haghi,
Janine Woehlk,
Azam Mohsin,
Michael K. Okoreeh,
Priya Mathur,
Akinola Olumide Emmanuel,
Abu Osman,
Manisha Krishnan,
Samuel Morin,
Alexander T. Pearson,
Randy F. Sweis,
Joel Pekow,
Christopher Weber,
Khashayarsha Khazaie,
Fotini Gounari
Publication year - 2021
Publication title -
nature immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 9.074
H-Index - 388
eISSN - 1529-2916
pISSN - 1529-2908
DOI - 10.1038/s41590-021-00889-2
Subject(s) - wnt signaling pathway , inflammatory bowel disease , foxp3 , epigenetics , inflammation , biology , immunology , rar related orphan receptor gamma , catenin , cancer research , proinflammatory cytokine , chromatin , signal transduction , microbiology and biotechnology , disease , medicine , gene , genetics , immune system
The diversity of regulatory T (T reg ) cells in health and in disease remains unclear. Individuals with colorectal cancer harbor a subpopulation of RORγt + T reg cells with elevated expression of β-catenin and pro-inflammatory properties. Here we show progressive expansion of RORγt + T reg cells in individuals with inflammatory bowel disease during inflammation and early dysplasia. Activating Wnt-β-catenin signaling in human and murine T reg cells was sufficient to recapitulate the disease-associated increase in the frequency of RORγt + T reg 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 T reg cells. Activation of β-catenin signaling interferes with this function and promotes the disease-associated RORγt + T reg phenotype.