Canonical Wnt Signaling Negatively Modulates Regulatory T Cell Function
2013; Cell Press; Volume: 39; Issue: 2 Linguagem: Inglês
10.1016/j.immuni.2013.07.019
ISSN1097-4180
AutoresJorg van Loosdregt, Veerle Fleskens, Machteld M. Tiemessen, Michal Mokrý, Ruben van Boxtel, Jenny Meerding, Cornelieke Pals, Dorota Kurek, Miranda R.M. Baert, Eveline M. Delemarre, Andrea Gröne, Marian J.A. Groot Koerkamp, Alice J.A.M. Sijts, Edward E.S. Nieuwenhuis, Madelon M. Maurice, Johan H. van Es, Derk ten Berge, Frank C. P. Holstege, Frank J. T. Staal, Dietmar M. Zaiss, Berent J. Prakken, Paul J. Coffer,
Tópico(s)Immune Cell Function and Interaction
ResumoSummary 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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