Objectives Regulation of NK cell response in acute mouse cytomegalovirus (MCMV) infection is dependent on the fine balance of signals coming from activating and inhibitory receptors expressed on their cell surface. In order to sidestep antigen presentation and recognition by CD8+T cells, MCMV encodes immunoevasion proteins that downmodulate the expression of MHC class I on the surface of infected cells. However, by lowering interactions and triggering through inhibitory Ly49 receptors, this process makes infected cells prone to „missing-self“-mediated killing by NK cells. In spite of that, most of the laboratory mouse strains are not capable of controlling the acute MCMV infection. My working hypothesis was that this mechanism has evolved to prevent NK cell activation and killing by restoring ‘self’ signature and allowing the engagement of inhibitory Ly49 receptors by their natural ligands. The objective of this thesis was to characterize mechanisms which MCMV utilizes to avoid early „missing self“-dependent NK cell response and to determine the role of „missing self“-mediated recognition during in vivo control of MCMV infection and its influence on specific CD8 T cell response. Methods For the purpose of this disertation I established an assay with reporter cells expressing inhibitory Ly49 receptors. Activation of reporter cells was followed by GFP expression using flow cytometry, after co-cultivation with MCMV infected cells in order to determine the viral gene(s) responsible for the ligation of this receptor. I used functional tests and immunophenotyping to analyse the phenotype and function of NK cells after infection of mice with WT or Dm04 MCMV. Standard plaque assay was used to determine the ability of various mouse strains to control infection with WT MCMV or Dm04 MCMV and the role of NK cells. Results The data show that the ligation of inhibitory Ly49A receptor by m04/MHC I complex results in: (i) protection of WT MCMV infected cells from NK cell-mediated killing, (ii) impaired proliferation of NK cells in vivo and (iii) weak control of the virus titer in vivo 3 days post infection in mice of H-2k i H-2d haplotype. I used the viral model of „missing self“-mediated recognition in determining the role of the strong NK cell response in shaping the adaptive immune response and demonstrated that in BALB/c mice the strong NK cell response does not influence the efficacy of the CD8 T cell response. This is most likely due to the preserved number and function of conventional dendritic cells. Finally, I identified three novel MCMVspecific activating Ly49 receptors: Ly49P, Ly49L i Ly49D2, which recognize infected cells via m04/MHC I complex and an additional viral factor. Conclusion This thesis presents a novel mechanism employed by mouse cytomegalovirus, aimed to avoid NK cell response by expressing a protein complex to ligate inhibitory Ly49 receptor, inhibit the proliferative capacity of NK cells and the ability to control virus titer in vivo. This study is the first evidence for the physiological role of the „missing self“-mediated recognition in the context of viral infection. At the same time it points to the 3 activating Ly49 receptors specifically recognizing the same m04/MHC I complex.