학술논문
Canonical Wnt Signaling Negatively Modulates Regulatory T Cell Function
Document Type
Academic Journal
Author
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.
Source
Immunity. Aug 01, 2013 39(2):298-310
Subject
Language
English
ISSN
1074-7613
Abstract
SUMMARY: 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. HIGHLIGHTS