title: Dickkopf-3, a tissue-derived modulator of local T-cell responses.
abstract: The adaptive immune system protects organisms from harmful environmental insults. In parallel, regulatory mechanisms control immune responses in order to assure preservation of organ integrity. Yet, molecules involved in the control of T-cell responses in peripheral tissues are poorly characterized. Here, we investigated the function of Dickkopf-3 in the modulation of local T-cell reactivity. Dkk3 is a secreted, mainly tissue-derived protein with highest expression in organs considered as immune-privileged such as the eye, embryo, placenta, and brain. While T-cell development and activation status in naïve Dkk3-deficient mice was comparable to littermate controls, we found that Dkk3 contributes to the immunosuppressive microenvironment that protects transplanted, class-I mismatched embryoid bodies from T-cell-mediated rejection. Moreover, genetic deletion or antibody-mediated neutralization of Dkk3 led to an exacerbated experimental autoimmune encephalomyelitis (EAE). This phenotype was accompanied by a change of T-cell polarization displayed by an increase of IFNγ-producing T cells within the central nervous system. In the wild-type situation, Dkk3 expression in the brain was up-regulated during the course of EAE in an IFNγ-dependent manner. In turn, Dkk3 decreased IFNγ activity and served as part of a negative feedback mechanism. Thus, our findings suggest that Dkk3 functions as a tissue-derived modulator of local CD4(+) and CD8(+) T-cell responses.
authors.affiliation: Department of Molecular Immunology, German Cancer Research Center , Heidelberg , Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Meister
authors.affiliation: Department of Molecular Immunology, German Cancer Research Center , Heidelberg , Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Papatriantafyllou
authors.affiliation: Department of Molecular Pathology, German Cancer Research Center , Heidelberg , Germany.
authors.forename: Viola
authors.initials: V
authors.lastname: Nordström
authors.affiliation: Department of Medicine I and Clinical Chemistry, University of Heidelberg , Heidelberg , Germany.
authors.forename: Varun
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Department of Molecular Immunology, German Cancer Research Center , Heidelberg , Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Ludwig
authors.affiliation: Therapeutic Immunology Group, Sir William Dunn School of Pathology, University of Oxford , Oxford , UK.
authors.forename: Kathy O
authors.initials: KO
authors.lastname: Lui
authors.affiliation: Therapeutic Immunology Group, Sir William Dunn School of Pathology, University of Oxford , Oxford , UK.
authors.forename: Ashleigh S
authors.initials: AS
authors.lastname: Boyd
authors.affiliation: Department of Molecular Pathology, German Cancer Research Center , Heidelberg , Germany ; Department of Pathology, University Medical Center Mannheim, University of Heidelberg , Mannheim , Germany.
authors.forename: Zoran V
authors.initials: ZV
authors.lastname: Popovic
authors.affiliation: Department of Medicine I and Clinical Chemistry, University of Heidelberg , Heidelberg , Germany.
authors.forename: Thomas Henry
authors.initials: TH
authors.lastname: Fleming
authors.affiliation: Department of Molecular Immunology, German Cancer Research Center , Heidelberg , Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Moldenhauer
authors.affiliation: Department of Medicine I and Clinical Chemistry, University of Heidelberg , Heidelberg , Germany.
authors.forename: Peter P
authors.initials: PP
authors.lastname: Nawroth
authors.affiliation: Department of Molecular Pathology, German Cancer Research Center , Heidelberg , Germany.
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.affiliation: Therapeutic Immunology Group, Sir William Dunn School of Pathology, University of Oxford , Oxford , UK.
authors.forename: Herman
authors.initials: H
authors.lastname: Waldmann
authors.affiliation: Department of Molecular Immunology, German Cancer Research Center , Heidelberg , Germany.
authors.forename: Thilo
authors.initials: T
authors.lastname: Oelert
authors.affiliation: Department of Molecular Immunology, German Cancer Research Center , Heidelberg , Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Arnold
keywords: Dickkopf-3; T cells; autoimmunity; immune privilege; transplantation