title: Canonical Wnt signaling negatively modulates regulatory T cell function.
abstract: 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.
authors: Department of Immunology, University Medical Center Utrecht, Utrecht 3584EA, The Netherlands.
authors: Jorg
authors: J
authors: van Loosdregt
authors: Veerle
authors: V
authors: Fleskens
authors: Machteld M
authors: MM
authors: Tiemessen
authors: Michal
authors: M
authors: Mokry
authors: Ruben
authors: R
authors: van Boxtel
authors: Jenny
authors: J
authors: Meerding
authors: Cornelieke E G M
authors: CE
authors: Pals
authors: Dorota
authors: D
authors: Kurek
authors: Miranda R M
authors: MR
authors: Baert
authors: Eveline M
authors: EM
authors: Delemarre
authors: Andrea
authors: A
authors: Gröne
authors: Marianne J A Groot
authors: MJ
authors: Koerkamp
authors: Alice J A M
authors: AJ
authors: Sijts
authors: Edward E S
authors: EE
authors: Nieuwenhuis
authors: Madelon M
authors: MM
authors: Maurice
authors: Johan H
authors: JH
authors: van Es
authors: Derk
authors: D
authors: Ten Berge
authors: Frank C
authors: FC
authors: Holstege
authors: Frank J T
authors: FJ
authors: Staal
authors: Dietmar M W
authors: DM
authors: Zaiss
authors: Berent J
authors: BJ
authors: Prakken
authors: Paul J
authors: PJ
authors: Coffer
mesh_terms: D000818:Animals; D001168:Arthritis / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003092:Colitis / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013582:Synovial Fluid / Q000166:cytology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D060449:Wnt Signaling Pathway; D060509:Wnt3A Protein / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; C555510:WNT3A protein, human; D060509:Wnt3A Protein; D051176:beta Catenin