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

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.