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Dickkopf-3, a Tissue-Derived Modulator of Local T-Cell Responses

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....

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Autores principales: Meister, Michael, Papatriantafyllou, Maria, Nordström, Viola, Kumar, Varun, Ludwig, Julia, Lui, Kathy O., Boyd, Ashleigh S., Popovic, Zoran V., Fleming, Thomas Henry, Moldenhauer, Gerhard, Nawroth, Peter P., Gröne, Hermann-Josef, Waldmann, Herman, Oelert, Thilo, Arnold, Bernd
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338807/
https://www.ncbi.nlm.nih.gov/pubmed/25759692
http://dx.doi.org/10.3389/fimmu.2015.00078
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author Meister, Michael
Papatriantafyllou, Maria
Nordström, Viola
Kumar, Varun
Ludwig, Julia
Lui, Kathy O.
Boyd, Ashleigh S.
Popovic, Zoran V.
Fleming, Thomas Henry
Moldenhauer, Gerhard
Nawroth, Peter P.
Gröne, Hermann-Josef
Waldmann, Herman
Oelert, Thilo
Arnold, Bernd
author_facet Meister, Michael
Papatriantafyllou, Maria
Nordström, Viola
Kumar, Varun
Ludwig, Julia
Lui, Kathy O.
Boyd, Ashleigh S.
Popovic, Zoran V.
Fleming, Thomas Henry
Moldenhauer, Gerhard
Nawroth, Peter P.
Gröne, Hermann-Josef
Waldmann, Herman
Oelert, Thilo
Arnold, Bernd
author_sort Meister, Michael
collection PubMed
description 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.
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spelling pubmed-43388072015-03-10 Dickkopf-3, a Tissue-Derived Modulator of Local T-Cell Responses Meister, Michael Papatriantafyllou, Maria Nordström, Viola Kumar, Varun Ludwig, Julia Lui, Kathy O. Boyd, Ashleigh S. Popovic, Zoran V. Fleming, Thomas Henry Moldenhauer, Gerhard Nawroth, Peter P. Gröne, Hermann-Josef Waldmann, Herman Oelert, Thilo Arnold, Bernd Front Immunol Immunology 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. Frontiers Media S.A. 2015-02-24 /pmc/articles/PMC4338807/ /pubmed/25759692 http://dx.doi.org/10.3389/fimmu.2015.00078 Text en Copyright © 2015 Meister, Papatriantafyllou, Nordström, Kumar, Ludwig, Lui, Boyd, Popovic, Fleming, Moldenhauer, Nawroth, Gröne, Waldmann, Oelert and Arnold. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Meister, Michael
Papatriantafyllou, Maria
Nordström, Viola
Kumar, Varun
Ludwig, Julia
Lui, Kathy O.
Boyd, Ashleigh S.
Popovic, Zoran V.
Fleming, Thomas Henry
Moldenhauer, Gerhard
Nawroth, Peter P.
Gröne, Hermann-Josef
Waldmann, Herman
Oelert, Thilo
Arnold, Bernd
Dickkopf-3, a Tissue-Derived Modulator of Local T-Cell Responses
title Dickkopf-3, a Tissue-Derived Modulator of Local T-Cell Responses
title_full Dickkopf-3, a Tissue-Derived Modulator of Local T-Cell Responses
title_fullStr Dickkopf-3, a Tissue-Derived Modulator of Local T-Cell Responses
title_full_unstemmed Dickkopf-3, a Tissue-Derived Modulator of Local T-Cell Responses
title_short Dickkopf-3, a Tissue-Derived Modulator of Local T-Cell Responses
title_sort dickkopf-3, a tissue-derived modulator of local t-cell responses
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338807/
https://www.ncbi.nlm.nih.gov/pubmed/25759692
http://dx.doi.org/10.3389/fimmu.2015.00078
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