Membrane-bound Dickkopf-1 in Foxp3+ regulatory T cells suppresses T-cell-mediated autoimmune colitis

Wook Jin Chae, Jong Hyun Park, Octavian Henegariu, Saliha Yilmaz, Liming Hao, Alfred L.M. Bothwell

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Induction of tolerance is a key mechanism to maintain or to restore immunological homeostasis. Here we show that Foxp3+ regulatory T (Treg) cells use Dickkopf-1 (DKK-1) to regulate T-cell-mediated tolerance in the T-cell-mediated autoimmune colitis model. Treg cells from DKK-1 hypomorphic doubleridge mice failed to control CD4+ T-cell proliferation, resulting in CD4 T-cell-mediated autoimmune colitis. Thymus-derived Treg cells showed a robust expression of DKK-1 but not in naive or effector CD4 T cells. DKK-1 expression in Foxp3+ Treg cells was further increased upon T-cell receptor stimulation in vitro and in vivo. Interestingly, Foxp3+ Treg cells expressed DKK-1 in the cell membrane and the functional inhibition of DKK-1 using DKK-1 monoclonal antibody abrogated the suppressor function of Foxp3+ Treg cells. DKK-1 expression was dependent on de novo protein synthesis and regulated by the mitogen-activated protein kinase pathway but not by the canonical Wnt pathway. Taken together, our results highlight membrane-bound DKK-1 as a novel Treg-derived mediator to maintain immunological tolerance in T-cell-mediated autoimmune colitis.

Original languageEnglish (US)
Pages (from-to)265-275
Number of pages11
JournalImmunology
Volume152
Issue number2
DOIs
StatePublished - Oct 2017
Externally publishedYes

Keywords

  • Dickkopf-1
  • autoimmune colitis
  • regulatory T cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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