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Expression of NKG2D ligand by cytomegalovirus enhances virus immunogenicity and vaccine efficacy

CD8+ T cells play a key role in the control of infections by viruses and other intracellular pathogens. During the early days of infection, the number of specific CD8+ T cells increases through intensive proliferation followed by a contraction phase and the generation of a stable pool of long-lived memory CD8+ T cells. For a number of pathogens the immunity induced after natural infection does not guarantee a complete protection against re-infection and disease, and successful vaccines are needed to induce a level of protection which is superior to the one that remains after natural infection. In recent years we have witnessed a significant progress in our understanding of the role of NK cells and other innate immune response mechanisms in regulating the magnitude and longevity of antigen specific T cell responses. In addition to their direct function in the containment of viral infection, a large body of published data suggests that NK cells play a role in shaping the specific immune response (Babic, Krmpotic et al. 2011, Vivier, Raulet et al. 2011, Biron 2012). NKG2D is one of the most important activating NK cell receptors and is also expressed on CD8+ T cells, γδ T cells, and some CD4+ T cells. While on NK cells NKG2D acts as a major activating receptor, when expressed on CD8+ T cells it has a co-stimulatory function (Diefenbach, Tomasello et al. 2002, Vivier, Tomasello et al. 2002). NKG2D recognizes a wide array of ligands, structurally related to MHC-I molecules, but with different expression patterns and modes of regulation. NKG2D ligands expression is driven by cellular stress, such as infection or tumor transformation (Cerwenka and Lanier 2003). The significance of NKG2D in the immune response against cytomegalovirus (CMV) infection is best illustrated by the fact that human CMV (HCMV) and MCMV have developed numerous immune evasion mechanisms against this receptor (Jonjic, Babic et al. 2008, Wilkinson, Tomasec et al. 2008). We have recently demonstrated that the infection of mice with a recombinant virus expressing the NKG2D ligand RAE-1γ results in a profound virus attenuation during the first days post infection due to NK cell activation via NKG2D, without affecting the magnitude of the MCMV-specific CD8+ T-cell response (Slavuljica, Busche et al. 2010). Challenge infection experiments indicate that the protection obtained after immunization with RAE-1γMCMV was vastly superior to the protection observed after immunization with wild-type MCMV. Even more striking results were observed in C57BL/6 mice infected with RAE-1γMCMV. The enhancement of priming by the expression of RAE-1γ on infected cells may also involve co-stimulation by engaging NKG2D expressed on CD8+ T cells (Markiewicz, Carayannopoulos et al. 2005). By doing so, NKG2D signaling may substitute CD28 signaling, which is compromised in MCMV infection (Markiewicz, Carayannopoulos et al. 2005). Our current study indicated that MCMV expressing RAE-1γ has a tremendous potential for boosting the efficiency of CD8+ T cells directed against a vectored antigenic peptide. Altogether, our data set the stage for powerful new approach in designing T-cell based vaccines vectors.

NKG2D ligand; cytomegalovirus; CD8+T cells

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