Alphaherpesviruses represent the largest herpesvirus subfamily and contain several important pathogens of man and animal, including herpes simplex virus in man and pseudorabies virus (PRV) in pigs. Natural killer (NK) cells are innate immune cells that are of particular importance during herpesvirus infections. NK cell activity is mainly regulated by activating and inhibitory receptors on their cell surface. One of the most potent activating NK cell receptors is NKG2D, which binds stress-induced ligands on the surface of e.g. virus-infected cells. Recently, we discovered that the conserved viral UL13 protein kinase of PRV triggers downregulation of NKG2D ligands, which represents the first identification of an alphaherpesvirus protein that triggers NKG2D ligand downregulation. The aims of the current PhD proposal are to (i) unravel the mechanism of UL13-induced NKG2D ligand downregulation, (ii) investigate whether this function of UL13 is conserved in other (alpha)herpesviruses and (iii) discover new porcine ligands for NKG2D and whether these are also downregulated by UL13. The data will generate new fundamental insights in the crucial interaction of herpesviruses with NK cells and may lead to applications in the design of vaccines and therapeutic viral vectors. In addition, the discovery of new porcine ligands for NKG2D is of particular importance in the context of pig-to-human xenotransplantation, since NKG2D on human NK cells contributes to lysis of porcine donor cells.