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Dickkopf-3, a tissue-derived modulator of local T-cell responses

Meister, M; Papatriantafyllou, M; Nordström, V; Kumar, V; Ludwig, J; Lui, KO; Boyd, A; ... Arnold, B; + view all (2015) Dickkopf-3, a tissue-derived modulator of local T-cell responses. Frontiers in Immunology , 6 , Article 78. 10.3389/fimmu.2015.00078. Green open access

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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.

Type: Article
Title: Dickkopf-3, a tissue-derived modulator of local T-cell responses
Open access status: An open access version is available from UCL Discovery
DOI: 10.3389/fimmu.2015.00078
Publisher version: https://doi.org/10.3389/fimmu.2015.00078
Language: English
Additional information: Copyright: © 2015 Meister, Papatriantafyllou, Nordström, Kumar, Ludwig, Lui, Boyd, Popovic, Fleming, Moldenhauer, Nawroth, Gröne, Waldmann, Oelert and Arnold. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) (http://creativecommons.org/licenses/by/4.0/). 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.
Keywords: Dickkopf-3, T cells, immune privilege, transplantation, autoimmunity
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci > Department of Surgical Biotechnology
URI: https://discovery.ucl.ac.uk/id/eprint/10113248
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