CD8+ T cells play a key role in the control of infections by intracellular pathogens. Recently, several top-notch studies provided ample evidence that NK cells are important in the regulation of CD8+ T cell response. NKG2D is an activating NK cell receptor which plays a role in the adaptive immune response by co-stimulating CD8+ T cells. Due to unique pattern of immune response, live attenuated CMVs are attractive candidates as vaccine vectors for a number of clinically relevant infections. The main idea behind this project stems from our preliminary data which suggest that a recombinant CMV vector expressing NKG2D ligand has a tremendous potential for subverting viral immunoevasion and boosting the efficiency of CD8 T cell response.
During the project we plan to systematically investigate the impact of all major innate immunity players on the CD8+ T cell response. A special focus will be given in obtaining new knowledge on the maintenance of memory CD8+ T cells during latent infection. This study will also provide novel insights on the role of NKG2D in both NK and T cell immunity. In order to test our hypothesis in vivo, we will employ state-of-the-art technology used in herpesvirus genetics coupled with high-end immune monitoring. Ultimately, we will translate our results to a human CMV vector, in order to gauge the impact of NKG2D signaling on immune response in a humanized mouse model.
We believe that the significance of the proposed study is enormous since stimulating CD8+ T cells has been widely recognized as a method of choice for vaccine development. There are relatively large number of pathogens for which the immunity acquired post-infection does not fully shelter against re-infection and disease. Therefore, we are in a desperate need for vaccines which offer superior protection compared to the one following natural infection. This study will provide groundbreaking information which will set the stage for the development of new vaccines and vaccine vectors.
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