Superior induction and maintenance of protective CD8 T cells in mice infected with mouse cytomegalovirus vector expressing RAE-1γ

Abstract

Due to a unique pattern of CD8 T-cell response induced by cytomegaloviruses (CMVs), live attenuated CMVs are attractive candidates for vaccine vectors for a number of clinically relevant infections and tumors. NKG2D is one of the most important activating NK cell receptors that plays a role in costimulation of CD8 T cells. Here we demonstrate that the expression of CD8 T-cell epitope of Listeria monocytogenes by a recombinant mouse CMV (MCMV) expressing the NKG2D ligand retinoic acid early-inducible protein 1-gamma (RAE-1γ) dramatically enhanced the effectiveness and longevity of epitope-specific CD8 T-cell response and conferred protection against a subsequent challenge infection with Listeria monocytogenes. Unexpectedly, the attenuated growth in vivo of the CMV vector expressing RAE-1γ and its capacity to enhance specific CD8 T-cell response were preserved even in mice lacking NKG2D, implying additional immune function for RAE-1γ beyond engagement of NKG2D. Thus, vectors expressing RAE-1γ represent a promising approach in the development of CD8 T-cellbased vaccines.RAE-1 gamma | CD8 T cell vaccine | vaccine vector A lthough vaccination plays a tremendous role in protection against infectious diseases, there are many pathogens for which even the immunity acquired after natural infection does not fully protect against reinfection and disease. Therefore, vaccines which offer superior protection compared with the protection following natural infection are needed. Most of the current vaccines induce protective antibodies but often fail to confer sufficient protection. An alternative approach is to develop vaccines which are based on the induction of cellular immunity in general and cytotoxic CD8 T cells in particular (1).Cytomegaloviruses (CMVs) are excellent inducers of the CD8 T-cell response, despite having numerous immunoevasion strategies aimed at compromising antigen presentation by MHC class I molecules (2). Preferentially, CMVs induce the effector arm of memory CD8 T cells (3). This, together with a large genome allowing the insertion of multiple foreign genes, makes CMVs attractive vaccine vectors. The outstanding capacity of specific CD8 T cells induced by CMV vectors was proven by studies demonstrating the role of tissue-resident effector memory CD8 T cells in the protection against challenge infection (4, 5). The suitability of CMV as a vaccine vector was further emphasized in a recent study by Hansen et al. (6).NKG2D is a receptor expressed on several lymphocyte subsets, with a predominant role in activation of NK cells. In addition, NKG2D has a costimulatory role on CD8 T cells (7). The ligands for the NKG2D receptor are several molecules induced by stress or cell transformation. In mice, NKG2D ligands comprise the RAE-1 family (RAE-1α-e), H60 family (H60a-c), and MULT-1 proteins (8). The significance of NKG2D signaling in immune response to CMV infection is best illustrated by numerous strategies used by CMVs to evade the function of this receptor (9). We have recently shown that infection of mice wi...

NKG2D Receptor and Its Ligands in Host Defense

“…Chimeric antigen receptors expressing the extracellular domain of NKG2D linked to the signaling elements of CD3ζ and DAP10 have been constructed and transduced into T cells to test their potential for cancer therapy (reviewed in (77)). As therapeutics in infectious disease, Jonjic and colleagues have introduced a cDNA encoding a NKG2D ligand into the mouse CMV genome and showed that it functions as an effective vaccine for CMV (78). These findings suggest a new strategy for the development of vaccines against pathogens that have been refractory to conventional approaches.…”

Activation of Innate and Adaptive Immunity by a Recombinant Human Cytomegalovirus Strain Expressing an NKG2D Ligand

“…Accordingly, genetically modified animal CMVs lacking immunoevasins exhibited outstanding vaccine properties in mouse and guinea pig models [30, 31]. Recently, we found that a mouse CMV (MCMV) expressing a host ligand for the activating receptor NKG2D induces an efficient CD8+ T cell response despite being profoundly attenuated [15, 32]. Moreover, challenge infection experiments indicated that the protection obtained after immunization is superior to the one seen after natural infection [15, 32].…”

Natural Killer Cell Evasion Is Essential for Infection by Rhesus Cytomegalovirus

“…In fact, replacement of m152 with the murine NKG2DL Rae-1 increased CD8 + T cell responses to MCMV [19, 20]. This is in stark contrast to the complete absence of T cell responses observed in CMV-naïve animals inoculated with ΔRh159.…”