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

Immunology. 2017 Oct;152(2):265-275. doi: 10.1111/imm.12766. Epub 2017 Jun 27.

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.

Keywords: Dickkopf-1; autoimmune colitis; regulatory T cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adoptive Transfer
  • Animals
  • Autoimmune Diseases / genetics
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / metabolism*
  • Autoimmune Diseases / pathology
  • Autoimmunity
  • CHO Cells
  • Cell Membrane / immunology
  • Cell Membrane / metabolism*
  • Cell Proliferation
  • Colitis / genetics
  • Colitis / immunology
  • Colitis / metabolism*
  • Colitis / pathology
  • Colon / immunology
  • Colon / metabolism*
  • Colon / pathology
  • Cricetulus
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • Disease Models, Animal
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / immunology
  • Forkhead Transcription Factors / metabolism*
  • Genetic Predisposition to Disease
  • Intercellular Signaling Peptides and Proteins / deficiency
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / immunology
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Lymphocyte Activation
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases / metabolism
  • Phenotype
  • Self Tolerance*
  • Signal Transduction
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism*
  • T-Lymphocytes, Regulatory / transplantation
  • Time Factors
  • Transfection

Substances

  • DNA-Binding Proteins
  • Dkk1 protein, mouse
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Rag2 protein, mouse
  • Mitogen-Activated Protein Kinases