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

Michael Meister,Viola Nordstrã¶M,Thilo Oelert,Bernd Arnold,Julia Ludwig,Herman Waldmann,Maria Papatriantafyllou,Thomas Henry Fleming,Zoran V Popovic,Ashleigh S Boyd,Varun Kumar,Kathy O Lui,Hermann-Josef Grã¶Ne,Gerhard Moldenhauer,Peter P Nawroth

doi:10.3389/fimmu.2015.00078

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.

Highlights

Adaptive immune responses in vital organs have to be precisely coordinated in order to assure proper pathogen clearance and at the same time, to prevent extended immune-mediated inflammation that might impair their function
Our findings provide strong evidence that Dkk3 contributes to the immunoregulatory properties of the tissue microenvironment and may provide a valuable target for immune intervention in autoimmunity, transplantation, and inflammatory disease
Frequencies of CD4+ CD25+ Foxp3+ regulatory T cells in the thymus were not altered in Dkk3−/− mice (Figure 1D)

Summary

Introduction

Adaptive immune responses in vital organs have to be precisely coordinated in order to assure proper pathogen clearance and at the same time, to prevent extended immune-mediated inflammation that might impair their function. This is essential for tissues with limited regenerative capacity such as the central nervous system (CNS), the eye, and the pregnant uterus. In these organs, extensive inflammation is prevented locally by mechanisms such as immune deviation away from destructive immune responses or by active suppression of inflammation. IDO is produced by several cell types in the eye [12, 13] and in the brain [14]

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Results

Conclusion