Role of the Hedgehog receptor Patched1 in the development and function of T lymphocytes
by Kai-David Michel
Date of Examination:2013-06-05
Date of issue:2013-06-18
Advisor:Prof. Dr. Holger Reichardt
Referee:Prof. Dr. Holger Reichardt
Referee:Prof. Dr. Heidi Hahn
Referee:Prof. Dr. Matthias Dobbelstein
Persistent Address:
http://dx.doi.org/10.53846/goediss-3888
Files in this item
Name:Dissertation Michel.pdf
Size:1.03Mb
Format:PDF
The following license files are associated with this item:
Abstract
English
The hedgehog signalling pathway is a highly conserved key regulator of animal development and required for homeostasis of adult tissues both in invertebrates and vertebrates. In addition, a large number of studies have suggested that this pathway is also implicated in different aspects of vertebrate haematopoiesis and lymphopoiesis. Its precise role in this context however appears to be complex and conflicting data reported from different groups have prevented a comprehensive understanding of its implication. The aim of the study at hand was to further improve the understanding of Hh signalling and its involvement in the development and function of T cells which are a central component of the adaptive immune system. For this purpose, a mouse model was employed in which expression of the Hh receptor Ptch was ablated specifically in T cells. Since Ptch is known to be a negative regulator of Hh signalling, its inactivation was expected to activate the canonical Hh signalling pathway and thus affect T cell behaviour. However, it was found that Ptch ablation only marginally affected the development of thymocytes at the transition from the DP to the SP stage. This minor effect did not have any implications for the total number of peripheral T cells or for the composition of the T cell pool. Furthermore, the activation state of peripheral T cells was found to be unaltered upon Ptch ablation indicating that functional characteristics were not affected either. Indeed, different experimental approaches in vitro which focused on several key characteristics of mature T cell populations failed to reveal any impact of the Ptch inactivation. Similar results were obtained from analyses of Ptch-deficient T cells in several disease models in vivo thus confirming that T cell-intrinsic Ptch expression is dispensable for proper T cell function even under physiological conditions. Interestingly and contrary to the consensus view, it was found that Ptch ablation did not result in the activation of the canonical Hh signalling cascade. Although this discrepancy can be explained in several ways, it is most likely accounted for by the lack of primary cilia on T cells which have emerged as important initiation sites of different signalling pathways. This hypothesis is supported by several independent reports which demonstrated that ablation of another upstream pathway component in cells of the haematopoietic lineage did not cause pathway activation or affect development or function of these cells either. Taken together, this thesis presents comprehensive evidence that intrinsic expression of the Hh receptor Ptch is dispensable for intermediate and late T cell development as well as for T cell function both in vitro and in vivo. In addition, it suggests that intrinsic canonical Hh signalling in T cells is not required under physiological conditions either.
Keywords: Hedgehog; Patched1; T cells