Wnt-β-catenin activation epigenetically reprograms T reg cells in inflammatory bowel disease and dysplastic progression

Nat Immunol. 2021 Apr;22(4):471-484. doi: 10.1038/s41590-021-00889-2. Epub 2021 Mar 4.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Case-Control Studies
  • Cell Proliferation*
  • Cells, Cultured
  • Cellular Reprogramming*
  • Colitis, Ulcerative / genetics
  • Colitis, Ulcerative / immunology
  • Colitis, Ulcerative / metabolism*
  • Colitis-Associated Neoplasms / genetics
  • Colitis-Associated Neoplasms / immunology
  • Colitis-Associated Neoplasms / metabolism*
  • Crohn Disease / genetics
  • Crohn Disease / immunology
  • Crohn Disease / metabolism*
  • Cytokines / genetics
  • Cytokines / metabolism
  • Disease Models, Animal
  • Epigenesis, Genetic*
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation, Neoplastic
  • Hepatocyte Nuclear Factor 1-alpha / genetics
  • Hepatocyte Nuclear Factor 1-alpha / metabolism
  • Humans
  • Lymphocyte Activation*
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Phenotype
  • T Cell Transcription Factor 1
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism*
  • Wnt Signaling Pathway*

Substances

  • Cytokines
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Hepatocyte Nuclear Factor 1-alpha
  • Hnf1a protein, mouse
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • RORC protein, human
  • Rorc protein, mouse
  • T Cell Transcription Factor 1
  • TCF7 protein, human