Journal
IMMUNITY
Volume 39, Issue 2, Pages 298-310Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2013.07.019
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Funding
- Dutch Rheumatism Foundation (Reumafonds)
- American Institute for Cancer Research (AICR)
- VENI-ZonMW
- Center for Translational Molecular Medicine
- TOP grant from the Netherlands Organisation for Health Research and Development
- KiKA
- AICR
- Dutch Cancer Society [2006-3508]
- Utrecht University (High Potential Programme)
- European Research Council [242958]
- European Research Council (ERC) [242958] Funding Source: European Research Council (ERC)
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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.
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