TY  - GEN
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/8825/
N2  - Protection of tissues from the devastating effects of immune responses is essential for the integrity of the organism. Tolerance mechanisms, such as T cell depletion or anergy induction by natural and adaptive regulatory T cells, tolerogenic dendritic cells and parenchymal cells control potentially auto-reactive lymphocytes. In addition, organs that are particularly sensitive to damage by inflammation, so called immune privileged sites, are protected by tissue barriers and contain an immunosuppressive microenvironment. There is increasing evidence that processes establishing immune privilege overlap with those associated with tolerance induction. However, there is much yet to learn about the molecules with a role in immune regulation. This knowledge could help in the understanding of systemic diseases, such as autoimmunity and cancer, and introduce novel principles concerning transplantation tolerance. Aim of this study was the identification of novel molecules that are potential mediators of peripheral tolerance. Starting from a transgenic mouse model for peripheral CD8 T cell tolerance, identification of such candidate genes was attempted by wide range gene expression analysis. Dickkopf 3 (Dkk3) was 10-fold upregulated in regulatory CD8 T cells. Interestingly, Dkk3 mRNA was previously shown to be present in peripheral tissues, such as the brain, the eye, the spinal cord, the ovary and the uterus, pointing to a possible role in immune privilege. Moreover, Dkk3 was reported to inhibit the ERK MAPK pathway in tumor cells, which is also crucial for T cell receptor signal transduction. Taking all the above into consideration, it was hypothesized that Dkk3 might be involved in immune regulation. Here, Dkk3 was identified as a novel modulator of immune responses. Dkk3 protein was shown to be expressed by the transgenic regulatory CD8 T cells and was indispensable for the suppression of naïve T cells. In detail, Dkk3 deficient transgenic mice displayed no CD8 T cell tolerance and regulatory CD8 T cells could not exert their suppressive function in the presence of anti-Dkk3 blocking antibody. The immune regulatory function of Dkk3 was not limited to the transgenic mouse model of CD8 T cell tolerance. Polyclonal T cells from Dkk3 deficient mice showed hyperproliferation and increased IL-2 production. This effect could be explained by the fact that the ERK MAPK is overactivated in the absence of Dkk3. Among the tissues that express Dkk3 in high amounts are the immune privileged organs(central nervous system (CNS), ovaries, placenta), the liver, which is a crucial site for the establishment of T cell tolerance to oral antigens, the heart and the lung. On the other hand, Dkk3 expression could not be detected in the lymphoid organs and the serum. Given the observed suppressive activity of Dkk3. it might control potentially harmful T cell responses in the above mentioned immune privileged organs. Indeed, the immune regulatory role of Dkk3 in the CNS could be demonstrated in the context of experimental autoimmune encephalitis (EAE). Absence of neuron-derived Dkk3 led to severe and persistent EAE, due to lack of suppression of activated CD8 T cells. In addition, blocking of the secreted Dkk3 with the respective anti-Dkk3 antibody resulted in increased disease chronicity. In conclusion, Dkk3 is a universal immune regulator, employed by transgenic tolerant CD8 T cells and immune privileged organs in order to control excessive T cell responses.
KW  - Dickkopf 3 
KW  -  Peripheral T cell tolerance 
KW  -  immune privilege
Y1  - 2008///
TI  - Molecular Mechanisms of Peripheral T cell Tolerance : Identification of Dickkopf 3 as a novel immune modulator
AV  - public
ID  - heidok8825
A1  - Papatriantafyllou, Maria
ER  -