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  • Final Report Summary - STADVINN (Strengthening adaptive immunity via innate immunity: enhancing the CD8 T cell response by using the NKG2D ligand expressed in a herpesvirus vector)
ERC

StAdvInn Report Summary

Project ID: 322693
Funded under: FP7-IDEAS-ERC
Country: Croatia

Final Report Summary - STADVINN (Strengthening adaptive immunity via innate immunity: enhancing the CD8 T cell response by using the NKG2D ligand expressed in a herpesvirus vector)

Cytomegaloviruses (CMVs) are known to induce unique pattern of immune response, making live, attenuated CMVs attractive candidates as vaccine vectors for a number of clinically relevant diseases. NKG2D is an activating NK cell receptor which also plays a role in the adaptive immune response by co-stimulating CD8 T cells. The main idea behind this project was based on our previous findings showing that murine CMV (MCMV) down-regulates all NKG2D ligands and our initial data suggesting that a recombinant CMV vector expressing the NKG2D ligand RAE-1γ in place of its viral inhibitor (Rae-1γMCMV) has tremendous potential for subverting viral immunoevasion. The results have clearly shown that the expression of NKG2D ligands in the MCMV vectors lacking the viral inhibitors of these cellular proteins strongly attenuated the virus even in an immunologically immature host such as newborn mice. This early attenuation was mainly NKG2D and NK cell dependent. However, the immune response to vectored antigens was either unaffected or even enhanced in the case of some CD8 T cell epitopes. Several MCMV vectors expressing CD8 T cell epitopes of various pathogens have been constructed (Listeria monocytogenes, respiratory syncytial virus, Francisella tularensis, Influenza A virus). An excellent protective capacity of CMV vectors expressing NKG2D ligands has been proven not only in the models of infectious diseases, but in tumor models as well. The most impressive property of immunization with a recombinant Rae-1γMCMV was the induction of high frequency of effector CD8 T cells which express KLRG1, which are nevertheless fully functional and able to secrete IFN-γ and degranulate. An unexpected finding of our study was that the enhanced CD8 T cell response to recombinant Rae-1γMCMV is independent of the NKG2D receptor. Even though we have made significant efforts to elucidate the NKG2D-independent function of RAE-1γ by different approaches, including mass spectrometry, screening of protein-protein interactions as well as transcriptomic analysis, the ultimate mechanism still awaits to be determined.
We also established excellent properties of CMV expressing NKG2D ligand as CMV vaccine in a model of congenital CMV infection of CNS. Similar to congenital infection with human CMV (HCMV), mice infected as newborns display various developmental and inflammatory lesions in their brains. In the frame of this project, we have shown that vaccination of female mice with MCMV expressing either RAE-1 or MULT-1 NKG2D ligand results in complete antibody-dependent protection of their offspring against challenge infection with MCMV. Moreover, in contrast to wild-type MCMV, infection of newborn mice with MCMV expressing NKG2D ligand MULT-1 failed to induce brain inflammation and delayed migration of neurons from the cerebellar external granular layer.
We also constructed recombinant HCMV carrying human NKG2D ligand ULBP2 in the place of its inhibitor UL16. To assess immunobiology of such virus, we established a model of humanized NSG mice and confirmed the main findings obtained using the MCMV model. To further translate these fundamental discoveries into clinically relevant models, we have also constructed a recombinant HCMV-ULBP2 vaccine vector expressing human glioblastoma neoantigens to be tested in a humanized mouse model.

Reported by

SVEUCILISTE U RIJECI, MEDICINSKI FAKULTET
Croatia
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