Kurzfassung

Natural killer (NK) cells of the innate immune system are potent effector cells for immunsurveillance of malignantly transformed cells. Their cytotoxicity depends on the balance of activating and inhibitory signals mediated by receptors on NK cells and the corresponding ligands. The analysis of the receptor-ligand interactions is critical to understand the cytotoxicity of NK cells against malignantly transformed cells as well as mechanisms of tumor immune escape. NKp30, which belongs to the...Natural killer (NK) cells of the innate immune system are potent effector cells for immunsurveillance of malignantly transformed cells. Their cytotoxicity depends on the balance of activating and inhibitory signals mediated by receptors on NK cells and the corresponding ligands. The analysis of the receptor-ligand interactions is critical to understand the cytotoxicity of NK cells against malignantly transformed cells as well as mechanisms of tumor immune escape. NKp30, which belongs to the family of natural cytotoxicity receptors, is critical for the cytotoxicity of NK cells against different targets, including malignantly transformed cells, virus-infected cells and dendritic cells (DCs). Although the crystal structure of NKp30 was recently solved, important molecular determinants of ligand recognition remain to be investigated. Previous work of my group showed that the stalk domain of NKp30 is important for ligand binding and indispensable for receptor signaling. Moreover, we could demonstrate that the stalk domain of NKp30 promotes homo-oligomerization of the ectodomain of NKp30 and increases the apparent ligand binding affinity of NKp30. Within the current research proposal, we aim at identifying key amino acid residues of the stalk domain, which are essential for receptor oligomerization and signaling. Moreover, we will investigate the influence of the NKp30 stalk domain on the dynamics and oligomeric state of NKp30 within the plasma membrane by single molecule tracking and high resolution microscopy (cooperation with Prof. Dr. Jacob Piehler, University of Osnabrück). These experiments will include analyses of the dynamic crosstalk between individual NKp30 molecules, NKp30 and CD3zeta as well as NKp30 and other NCRs. NKp30 is a target for immune evasion of tumor cells. We have previously shown that a soluble domain of BAG-6 (BAG-6(686-936)) represents the binding site for NKp30 and acts as an inhibitory ligand for NKp30. Therefore, we aim at investigating full-length BAG-6 and its role in tumor escape from NKp30-dependent NK cell immunosurveillance. Results from these experiments will provide first molecular evidence for full-length BAG-6 as an immunoevasin targeting NKp30-dependent NK cell cytotoxicity.
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