Canonical Wnt Signaling Negatively Modulates Regulatory T Cell Function

• Published in: Immunity (Cambridge, Mass.) Mass.), 2013-08, Vol.39 (2), p.298-310
• Main Authors: van Loosdregt, Jorg, Fleskens, Veerle, Tiemessen, Machteld M., Mokry, Michal, van Boxtel, Ruben, Meerding, Jenny, Pals, Cornelieke E.G.M., Kurek, Dorota, Baert, Miranda R.M., Delemarre, Eveline M., Gröne, Andrea, Koerkamp, Marianne J.A. Groot, Sijts, Alice J.A.M., Nieuwenhuis, Edward E.S., Maurice, Madelon M., van Es, Johan H., ten Berge, Derk, Holstege, Frank C., Staal, Frank J.T., Zaiss, Dietmar M.W., Prakken, Berent J., Coffer, Paul J.
• Format: Article
• Language: English
• Subjects: Animals; Arthritis - immunology; beta Catenin - genetics; beta Catenin - metabolism; Cell Proliferation; Cells, Cultured; Colitis - immunology; Experiments; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; HEK293 Cells; Hepatocyte Nuclear Factor 1-alpha - genetics; Hepatocyte Nuclear Factor 1-alpha - metabolism; Humans; Inflammatory bowel disease; Kinases; Lymphocytes; Medical research; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Proteins; Rodents; Statistical analysis; Synovial Fluid - cytology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Transcription factors; Wnt Signaling Pathway; Wnt3A Protein - metabolism
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2013.07.019

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. •TCF/β-catenin and Foxp3 share common transcriptional targets•Wnt signaling negatively modulates Foxp3 transcriptional activity•Wnt signaling reduces Treg-cell-mediated suppression in vitro and in vivo•Wnt production is increased upon the activation of T cells and at inflammatory loci