TY  - GEN
A1  - Hoffmann, Sabrina
N2  - Natural killer (NK) cells are able to attack and destroy tumorous or virally infected cells without prior sensitization. The processes that regulate their activation and function are still incompletely understood. NK cells do not exress a single clonal receptor like T-cells but many different activating and inhibitory receptors. Most of the inhibitory receptors bind to MHC I or related molecules. Some activating receptors recognize ligands induced upon cell stress or transformation. One group of inhibitory receptors on NK cells is constituted by the NKG2 family. Some of these receptors form antithetic pairs. That means, they recognize the same ligands but signal in a contrary fashion. One of the most important NKG2 receptors is NKG2D. For this receptor an antithetic counterpart has not been described yet.  One part of this thesis included the identification of a possible inhibitory counterpart for NKG2D. Data base searches retrieved the cDNA for CLEC12B. Characterization of the receptor lead to the result that it did not bind the known NKG2D ligands and was not expressed on NK cells. Nevertheless, it is able to confer inhibitory signaling via the recruitment of the tyrosine-phosphatases SHP-1 and SHP-2. Expression of the inhibitory receptor CLEC12B was detected on monocyte-derived macrophages.  Another important group of activating receptors is constituted by the natural cytotoxicity receptors (NCR). They have been implied in antiviral defense and in the recognition of malignant cells. Although the ligand remains unknown it is still possible to detect it by applying functional assays and staining methods using soluble fusion proteins. The role of the NCR ligands has up to now not been examined in human cytomegalovirus (HCMV) infection. Fusion protein staining and functional data presented in this thesis suggest that the NCR ligands are downregulated from the cell surface. This might constitute a new immune evasion mechanism of HCMV. It was discovered that this process is mediated by a viral gene product that is expressed de novo upon infection during the immediate early or early phase of infection. The creation of viral deletion mutants helped to exclude non-essential regions of the HCMV genome. Immunofluorescence staining with fusion proteins showed that the ligand is held back in intracellular compartments. For further research the elucidation of the NCR ligands is vitally important. Heparan sulfate structures have been postulated to function as ligands but these results are debated. In this thesis, it was established that heparan sulfate is not the functional ligand for NKp30. The putative ligand was found to involve a proteinacious component that is not GPI-anchored. It was tried to identify the NKp30 ligand with the help of a genomic siRNA library. Cells expressing the NKp30 ligand were transduced with the library and selected for cells with an NKp30 negative phenotype. The siRNAs were rescued from the cell population, amplified and analyzed via an affimetrix genechip. The results show the enrichment of some interesting transmembrane or secreted proteins as possible candidates that might function as ligand for NKp30.  
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/8155/
TI  - Target Recognition by Natural Killer Cells : Identification and Characterization of Inhibiting and Activating Factors
ID  - heidok8155
AV  - public
Y1  - 2008///
KW  - NKp30NKp30
ER  -