TY - JOUR
T1 - Canonical Wnt signaling negatively modulates regulatory T cell function
AU - vanLoosdregt, Jorg
AU - Fleskens, Veerle
AU - Tiemessen, Machteld M.
AU - Mokry, Michal
AU - vanBoxtel, Ruben
AU - Meerding, Jenny
AU - Pals, Cornelieke E.G.M.
AU - Kurek, Dorota
AU - Baert, Miranda R.M.
AU - Delemarre, Eveline M.
AU - Gröne, Andrea
AU - Koerkamp, Marianne J.A.Groot
AU - Sijts, Alice J.A.M.
AU - Nieuwenhuis, Edward E.S.
AU - Maurice, Madelon M.
AU - vanEs, Johan H.
AU - tenBerge, Derk
AU - Holstege, Frank C.
AU - Staal, Frank J.T.
AU - Zaiss, Dietmar M.W.
AU - Prakken, Berent J.
AU - Coffer, Paul J.
N1 - Funding Information:
The authors thank M. Klein for technical assistance and S. Sakaguchi, B. Burgering, M. van de Wetering, and A. Banham for providing us with plasmids. V.F. was supported by a grant from the Dutch Rheumatism Foundation (Reumafonds). M.M.T. was supported by the American Institute for Cancer Research (AICR) and VENI-ZonMW. R.v.B. was supported by the Center for Translational Molecular Medicine. F.J.T.S. was supported by a TOP grant from the Netherlands Organisation for Health Research and Development, KiKA, and the AICR. M.M.M. was supported by Dutch Cancer Society (2006-3508), Utrecht University (High Potential Programme), and the European Research Council (starting grant 242958).
PY - 2013/8/22
Y1 - 2013/8/22
N2 - 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 Tcell 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 invitro and invivo, whereas disruption of Wnt signaling in Treg cells enhanced their suppressive capacity. The activation of effector Tcells 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.
AB - 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 Tcell 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 invitro and invivo, whereas disruption of Wnt signaling in Treg cells enhanced their suppressive capacity. The activation of effector Tcells 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.
UR - https://www.scopus.com/pages/publications/84882692382
U2 - 10.1016/j.immuni.2013.07.019
DO - 10.1016/j.immuni.2013.07.019
M3 - Article
C2 - 23954131
AN - SCOPUS:84882692382
SN - 1074-7613
VL - 39
SP - 298
EP - 310
JO - Immunity
JF - Immunity
IS - 2
ER -