engleski

Immunobiology of a recombinant cytomegalovirus expressing the NKG2D ligand – an approach towards live attenuated vaccine and vaccine vector

NKG2D is a potent activating receptor expressed by cells of innate and adaptive immunity that recognizes cell surface molecules structurally related to MHC-I proteins, which are induced by infection and other types of cellular stress. The engagement of NKG2D leads to cytotoxicity and cytokine secretion by NK cells, or to costimulation of CD8+ T cells. Both human cytomegalovirus (CMV) and mouse CMV deploy evasive mechanisms to prevent the expression of NKG2D ligands on the cell surface. The importance of viral regulation of the NKG2D signaling pathway is further illustrated by the fact that several herpesviruses, including human CMV, also use microRNA to regulate the expression of NKG2D ligands. So far we have characterized four mouse CMV proteins involved in the down-modulation of NKG2D ligands in infected cells. The deletion of any of these viral immunoevasive genes involved in regulation of NKG2D ligands resulted in virus attenuation in vivo. Based on the attenuation of viruses lacking NKG2D immunoevasins, we have proposed the idea that the insertion of genes encoding for NKG2D ligands in the place of genes encoding their viral inhibitors could be an appropriate approach for the immunological attenuation of a live vaccine. We have recently shown that, despite the strong NK cell-mediated attenuation, mouse CMV engineered to express the NKG2D ligand RAE-1gamma elicits a strong and long-lasting antiviral CD8 response, providing protection against a lethal virus challenge (Slavujica et al, JCI 2010). In this talk I will review the current knowledge on CMV downregulation of NKG2D signaling and will present our recent results using CMV expressing NKG2D ligand as a live attenuated vaccine and vaccine vector.

recombinant cytomegalovirus; NKG2D ligand; vaccine; vaccine vector

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