Canonical Wnt signaling negatively modulates regulatory T cell function

Immunity. 2013 Aug 22;39(2):298-310. doi: 10.1016/j.immuni.2013.07.019. Epub 2013 Aug 15.


Foxp3 is crucial for both the development and function of regulatory T (Treg) cells; however, the posttranslational mechanisms regulating Foxp3 transcriptional output remain poorly defined. Here, we demonstrate that T cell factor 1 (TCF1) and Foxp3 associates in Treg cells and that active Wnt signaling disrupts Foxp3 transcriptional activity. A global chromatin immunoprecipitation sequencing comparison in Treg cells revealed considerable overlap between Foxp3 and Wnt target genes. The activation of Wnt signaling reduced Treg-mediated suppression both in vitro and in vivo, whereas disruption of Wnt signaling in Treg cells enhanced their suppressive capacity. The activation of effector T cells increased Wnt3a production, and Wnt3a levels were found to be greatly increased in mononuclear cells isolated from synovial fluid versus peripheral blood of arthritis patients. We propose a model in which Wnt produced under inflammatory conditions represses Treg cell function, allowing a productive immune response, but, if uncontrolled, could lead to the development of autoimmunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis / immunology*
  • Cell Proliferation
  • Cells, Cultured
  • Colitis / immunology*
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • HEK293 Cells
  • Hepatocyte Nuclear Factor 1-alpha / genetics
  • Hepatocyte Nuclear Factor 1-alpha / metabolism*
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Synovial Fluid / cytology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • Wnt Signaling Pathway
  • Wnt3A Protein / metabolism
  • beta Catenin / genetics
  • beta Catenin / metabolism


  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • HNF1A protein, human
  • Hepatocyte Nuclear Factor 1-alpha
  • WNT3A protein, human
  • Wnt3A Protein
  • beta Catenin

Associated data

  • GEO/GSE49199