Transgenic Expression of the Activating Natural Killer Receptor Ly49H Confers Resistance to Cytomegalovirus in Genetically Susceptible Mice

Nakajima

The Journal of Immunology

et al. 2007

CMV infection is one of the most common complications in immunocompromised individuals, such as organ and bone marrow transplant patients. Both innate and adaptive immune responses are required for defense against CMV infection. In murine CMV (MCMV) infection, strains harboring the MCMV-specific NK cell activation receptor, Ly49H (Klra8), are resistant. In contrast, MCMV infection of mice lacking Ly49H gene causes early mortality due to uncontrolled viral replication. In this study, we report the successful protection of mice from lethal MCMV infection with gene-transferred polyclonal CD8 T cells. CD8 T cells expressing a chimeric receptor comprising Ly49H extracellular and CD3ζ cytoplasmic domains are capable of killing target cells expressing the MCMV protein, m157. CD8 T cells expressing the chimeric receptor protect mice in vivo from lethality in the acute phase of MCMV infection, leading to the establishment of long-term protection. These data provide proof-of-principle evidence that a novel strategy for harnessing CD8 cytolytic function through TCR-independent yet pathogen-specific receptor can result in effective protection of hosts from pathogens.

supporting

confidence: 50%

Protection from Lethal Infection by Adoptive Transfer of CD8 T Cells Genetically Engineered to Express Virus-Specific Innate Immune Receptor

Nakajima

The Journal of Immunology

et al. 2007

“…Similarly, the sequence data confirm the absence of a Ly49h-related gene in BALB/c mice as previously suggested by the lack of a NK cell subset staining with Ly49H-specific antibodies and the increased splenic viral titer of BALB/c mice relative to B6 during MCMV infection. 5,26,27 Furthermore, the complete sequencing of the BALB/c Ly49 cluster indicates that the 5E6 mAb should only recognize Ly49C on NK cells in this inbred strain since the BALB/c allele for Ly49i is a pseudogene. Thus, the BALB/c mouse strain is superior to B6 in this respect, as all functional NK studies performed with B6 mice using the 5E6 antibody cannot differentiate between the contributions of Ly49C and I.…”

Section: Discussionmentioning

confidence: 99%

Complete elucidation of a minimal class I MHC natural killer cell receptor haplotype

Dewar

Ml³

et al. 2005

Genes Immun

The BALB/c inbred mouse is widely used in models of infectious disease, transplantation, and cancer. The differences in the immune responses of BALB/c compared to C57BL/6 mice are especially valuable for the identification of immune regulation genes. One striking immune variance between these mice is in the function of natural killer (NK) cells, and there is strong evidence implicating differential expression of Ly49 genes. In this study, the complete BALB/c Ly49 gene cluster has been sequenced and found to contain six functional genes and two pseudogenes. Compared to C57BL/6 mice, there is a 200 kb region absent in the BALB/c cluster including a complete lack of Ly49h-related genes, which explains the increased susceptibility of BALB/c to cytomegalovirus infection. In addition, there is no BALB/c Ly49d allele, explaining the inability of BALB/c NK cells to kill certain tumor cells. The Ly49 region has now been sequenced in three different inbred mouse strains, and comparisons indicate that the evolution of each haplotype is not straightforward and has involved large-scale deletions/ insertions, gene recombination, and unequal crossing over between divergent haplotypes. This study confirms that relatively small murine class I MHC receptor haplotypes exist, analogous to observations made of human killer cell Ig-like receptor gene haplotypes.

The Journal of Immunology

“…The Cmv1 r resistance locus for MCMV was determined to encode the NK cell activation receptor, Ly49H (6 -8). Mice expressing this NK cell receptor, such as C57BL/6 (B6) mice or BALB/c mice reconstituted with Ly49h by transgenesis, are significantly more resistant to MCMV infection than mice that lack Ly49H expression (3,6,7,9). Ly49H is a C-type lectin-like receptor whose expression and signaling are dependent on the ITAM-containing adaptor DAP12, also known as killer-activating receptor-associated protein or TYROBP (10,11).…”

Section: Dap12 Signaling Directly Augments Proproliferative Cytokine mentioning

confidence: 99%

DAP12 Signaling Directly Augments Proproliferative Cytokine Stimulation of NK Cells during Viral Infections

French

Sjölin

Kim

et al. 2006

NK cells vigorously proliferate during viral infections. During the course of murine CMV infection, this response becomes dominated by the preferential proliferation of NK cells that express the activation receptor Ly49H. The factors driving such selective NK cell proliferation have not been characterized. In this study, we demonstrate that preferential NK cell proliferation is dependent on DAP12-mediated signaling following the binding of Ly49H to its virally encoded ligand, m157. Ly49H signaling through DAP12 appears to directly augment NK cell sensitivity to low concentrations of proproliferative cytokines such as IL-15. The impact of Ly49H-mediated signaling on NK cell proliferation is masked in the presence of high concentrations of proproliferative cytokines that nonselectively drive all NK cells to proliferate.