Canonical Wnt Signaling Negatively Modulates Regulatory T Cell Function

被引：176

作者：

van Loosdregt, Jorg ^{[1
,2
,3
]}

Fleskens, Veerle ^{[1
,3
]}

Tiemessen, Machteld M. ^{[9
]}

Mokry, Michal ^{[4
]}

van Boxtel, Ruben ^{[3
]}

Meerding, Jenny ^{[2
,5
]}

Pals, Cornelieke E. G. M. ^{[1
,3
]}

Kurek, Dorota ^{[10
]}

Baert, Miranda R. M. ^{[9
]}

Delemarre, Eveline M. ^{[2
,5
]}

Groene, Andrea ^{[11
]}

Koerkamp, Marianne J. A. Groot

Sijts, Alice J. A. M. ^{[12
]}

Nieuwenhuis, Edward E. S. ^{[4
]}

Maurice, Madelon M. ^{[3
]}

van Es, Johan H. ^{[7
,8
]}

ten Berge, Derk ^{[10
]}

Holstege, Frank C. ^{[6
]}

Staal, Frank J. T.

Zaiss, Dietmar M. W. ^{[12
]}

Prakken, Berent J. ^{[2
,5
]}

Coffer, Paul J. ^{[1
,2
,3
]}

机构：

[1] Wilhelmina Childrens Hosp, Dept Immunol, Utrecht, Netherlands

[2] Wilhelmina Childrens Hosp, Ctr Mol & Cellular Intervent, Utrecht, Netherlands

[3] Wilhelmina Childrens Hosp, Dept Cell Biol, Utrecht, Netherlands

[4] Wilhelmina Childrens Hosp, Dept Pediat Gastroenterol, Utrecht, Netherlands

[5] Wilhelmina Childrens Hosp, Dept Pediat Immunol, Utrecht, Netherlands

[6] Univ Med Ctr Utrecht, NL-3584 EA Utrecht, Netherlands

[7] Hubrecht Inst KNAW, NL-3584 CT Utrecht, Netherlands

[8] Univ Med Ctr Utrecht, NL-3584 CT Utrecht, Netherlands

[9] Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, NL-2300 RC Leiden, Netherlands

[10] Erasmus Stem Cell Inst, Dept Cell Biol, NL-3015 GE Rotterdam, Netherlands

[11] Fac Vet Med Utrecht, Dept Pathobiol, NL-3508 TD Utrecht, Netherlands

[12] Fac Vet Med Utrecht, Dept Immunol & Infect Dis, NL-3508 TD Utrecht, Netherlands

来源：

IMMUNITY | 2013年 / 39卷 / 02期

基金：

欧洲研究理事会;

关键词：

BETA-CATENIN; STEM-CELLS; FOXP3; OCCUPANCY; LITHIUM-THERAPY; DIFFERENTIATION; STABILIZATION; ENTEROPATHY; ACTIVATION; EXPRESSION; ARTHRITIS;

D O I：

10.1016/j.immuni.2013.07.019

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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.

引用

页码：298 / 310

页数：13

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