Wnt–β-catenin activation epigenetically reprograms Treg cells in inflammatory bowel disease and dysplastic progression
- 4 March 2021
- journal article
- research article
- Published by Springer Nature in Nature Immunology
- Vol. 22 (4) , 471-484
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.Keywords
Funding Information
- Division of Intramural Research (R01AI108682, R01AI108682)
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (P30DK42086)
- Praespero autoimmunity Fund
- American Association of Immunologists
- U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD007009)
- U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (T32HL07605)
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