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The role of Dickkopf-3 in tissue mediated immune modulation

Meister, Michael

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The immune system protects our organism from harmful environmental insults. Pathogens induce innate and adaptive immune responses that resolve infection and clear damaged cells. A tight balance between efficient elimination of the initial insult and the containment of the immune response, assures protection of the organism as well as the preservation of organ integrity. Disregulation of this system can lead to devastating effects like tissue damage and organ failure caused by excessive inflammation. Tissue components play a pivotal role in the regulation of immune responses. In order to develop novel therapeutic strategies for the treatment of inflammatory diseases, their properties have to be incorporated. Hence, a detailed understanding of mechanisms by which tissue cells influence immune responses is indispensable. Recently, our lab identified Dickkopf-3 (Dkk3) as an immune modulator mainly expressed by tissue cells. Thus we aimed to uncover the contribution of Dkk3 to tissue mediated immune modulation during inflammation. With the help of a transgenic mouse model we investigated how antigen-presenting keratinocytes in the inflamed skin modulate T cell reactivity. In these mice, keratinocytes present a myelin basic protein (MBP) peptide only upon skin inflammation. In the absence of systemic MBP immunization acute skin inflammation resulted in keratinocyte-mediated activation of MBP-specific CD4+ T cells that were encephalitogenic. However, chronic skin inflammation limited the encephalitogenic potential of systemically primed MBP-specific T cells. In this setting Dickkopf-3 was indispensable for the limitation of CD4 T cell reactivity. We successfully generated a transgenic Dkk3 reporter mouse that reliably indicates sites of Dkk3 expression. Furthermore, in vitro and in vivo studies identified interferon-γ (IFNγ) as a potent regulator of Dkk3 expression in tissue cell. Finally, we found that Dkk3 promotes the development of renal fibrosis in 2 different mouse models, indicated by decreased severity of fibrosis in Dkk3 deficient mice. Furthermore, we observed that Dkk3 expression is induced in tubular epithelial cells in the course of fibrosis development. Less fibrosis in Dkk3 deficient mice was accompanied by elevated levels of pro-inflammatory cytokines and increased T cell infiltration in the respective kidneys. Additionally, we observed an altered polarization of infiltrating CD4 T cells towards a Th1/Treg phenotype in dkk3-/- kidneys, which came along with decreased expression of Wnt target genes in these cells. In conclusion, Dkk3 contributes to tissue mediated immune modulation by regulation of T cell responses.

Item Type: Dissertation
Supervisor: Arnold, Prof. Dr. Bernd
Date of thesis defense: 28 March 2014
Date Deposited: 20 Jun 2014 06:13
Date: 2014
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 500 Natural sciences and mathematics
610 Medical sciences Medicine
Controlled Keywords: Dickkopf-3, Immunology, Tissue
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