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Abstract

The immune system responds to an enormous variety of pathogens as well as to malignant cells. Since healthy tissues may also be damaged during immune responses, multiple mechanisms have evolved to shape and limit immune responses, in order to protect the integrity of the respective tissue. Understanding the basic mechanisms of immune regulation will help to successfully reprogram immune reactivity in immune-mediated diseases. T cell responses can be regulated by multiple factors including intrinsic and extrinsic modulators.

In the first part of this thesis we aimed to understand how the Nck adaptor proteins, as intrinsic modulators, control T cell effector function. Nck adaptor proteins stabilize proximal signaling complexes of T cell receptors (TCR) in the cytoplasm, thereby enhancing TCR signaling. We found that T cell-specific deletion of Nck proteins (Nck.T-/-) lead to impaired germinal center formation, which is the central event for productive T cell-dependent antibody production. The number of follicular helper T (Tfh) cells, which are essential for germinal center formation, was decreased in the spleen of Nck.T-/- mice in comparison to wild type controls. The production of cytokines, such as IL-4, IL-10, and IL-21, by Tfh cells was reduced. The dysfunction of Tfh cells was associated with decreased Akt phosphorylation and intensified apoptosis of Tfh cells. Consequently, T cell-dependent antibody responses were reduced in regard to quantity as well as quality by affinity maturation. Furthermore, using experimental autoimmune encephalomyelitis as an autoimmune model lower disease scores, delayed dynamics and faster recovery were observed in Nck.T-/- mice in comparison to wild type animals. Together, our findings show an essential role for the Nck adapter proteins in the generation of potent effector T cells. Thus, defects in Nck protein function may have a so far un-recognized role in human diseases with defective T cell responses.

The second part focused on the role of the secreted protein Dickkopf-3 (DKK3) in modulating T cell responses against transplanted tumors. Mesenchymal stem cells (MSCs) are known to limit T cell responses in vivo. We found that DKK3 is produced by MSCs and contributed to MSC-mediated immune-suppression. Wild type MSCs inhibited anti-tumor responses whereas DKK3 deficient MSCs did not affect the rejection process. Impaired chemokine production by DKK3-/- MSCs could be related to enhanced infiltration of CD8+ T cells within the DKK3-/- MSC-inoculated tumors. In addition, loss of DKK3 in MSCs resulted in increased expression of MHC class II antigens that may render MSCs more immunogenic rather than immune-suppressive. The higher expression of MHC II in DKK3-/- MSCs was associated with decreased mTOR activity and thereby enhanced autophagy. We hypothesize that DKK3 may act as a positive modulator of the non-canonical Wnt/PCP pathway. Presently, DKK3 is being suggested as a potential anti-tumoral agent in human cancers based on reports that DKK3 is a tumor-suppressor. Our studies showing an immune-suppressive effect of DKK3 in the tumor mass may counteract these optimistic expectations and call for further detailed studies on the role of DKK3 in tumor development and in the respective immune responses before starting clinical trials.

Together, our studies contribute to a better understanding of mechanisms, which are involved in the control of T cell responses, and open new perspectives for further investigations.