Deficient Major Histocompatibility Complex-Linked Innate Murine Cytomegalovirus Immunity in MA/My.L-H2^bMice and Viral Downregulation of H-2^kClass I Proteins

Abstract

NK cells are key effectors of innate immunity and host survival during cytomegalovirus (CMV) infection. Innate murine CMV (MCMV) resistance in MA/My mice requires Ly49H/m157-independent H-2k-linked NK cell control. Here we show that replacement of MA/My H-2k with C57L H-2b susceptibility genes led to a remarkable loss of innate virus immunity, though NK gamma interferon was induced in H-2b and H-2k strains shortly after infection. Thus, H-2b genes expressed in C57L or MA/My.L-H2b are sufficient in alerting NK cells to intrusion but fail to support NK restraint of viral infection. In addition, novel H-2 recombinant strains were produced and utilized in a further refinement of a critical genetic interval controlling innate H-2k-linked MCMV resistance. Importantly, this analysis excluded the gene interval from Kk class I through class II. The responsible gene(s) therefore resides in an interval spanning Dk class Ia and more-distal major histocompatibility complex (MHC) nonclassical class Ib genes. Recently, the NK activation receptor Ly49P and MHC class I Dk proteins were genetically implicated in MCMV resistance, in part because Ly49P-expressing reporter T cells could specifically bind Dk molecules on MCMV-infected mouse embryonic fibroblasts (MEFs). However, as we found that H-2k innate resistance differs in the C57L or MA/My backgrounds and because MCMV very efficiently downregulates H-2k class I proteins in L929 cells and primary MEFs shortly after infection, a Ly49P/Dk model should not fully explain H-2k-linked MCMV resistance.

Immune evasion of natural killer cells by viruses

“…Although the molecular nature of target recognition remains unknown, it is likely that the recognition of H-2D k molecules depends on the viral peptide. These conclusions are corroborated by Brown and colleagues [65]. Altogether, by its specificity for MHC class I allele and viral protein, Ly49P represents another highly specific mechanism of NK cell-mediated control.…”

Functional Consequences of Natural Sequence Variation of Murine Cytomegalovirus m157 for Ly49 Receptor Specificity and NK Cell Activation

“…Recent studies by Belanger et al (15) have shown that NOD mice possess a Ly49H activation receptor, but sequence differences from Ly49H B6 result in the failure to control MCMV infection. The evolutionary pressures driving the emergence of activating receptors from inhibitory Ly49 homologues may be due to interactions with more conserved molecules from other pathogens or to MHC class I molecules altered by virus infection, such as is the case for the recognition of H-2D k by the Ly49P activating receptor from MA/My mice (53)(54)(55), where the recognition of H-2D k is dependent on the expression of the MCMV-encoded m04 molecule (56). B6 mice are generally termed "resistant" (Cmv1 r ), but this is true only in the context of m157…”

Self MHC class I–licensed NK cells enhance adaptive CD8 T-cell viral immunity

“…Congenic and transgenic mice were genotyped as described previously using MHC genetic markers 17Mit16, 17Uva12, 17Uva17, 17Uva03,19 Virus studies and in vivo resistance assays Salivary gland stock virus (SGV) was prepared and titered on NIH3T3 monolayers as described. 15 Experimental mice (8-12 weeks) were infected intraperitoneally with 10 4 PFU MCMV, unless indicated otherwise. MCMV genomes in spleen samples were measured using quantitative real-time PCR as described.…”

“…[13][14][15] Classic genetics studies to examine MA/My virus resistance mapped genes to the MHC I D region on chromosome 17 and the NK gene complex (NKC) on chromosome 6. [15][16][17][18] Recently, we identified MHC I D k as a critical genetic factor, 19 and further demonstrated a requisite role of licensed Ly49G2 ϩ NK cells needed in MCMV resistance. 18,19 Consistent with a requirement for NK stimulatory signals, Ly49P has been shown to bind MHC I D k on infected cells displaying MCMV glycoprotein gp34.…”

“…12 In MA/My mice and other H-2 k strains, the MHC provides vital protection against lethal murine CMV (MCMV) infection. [13][14][15] Classic genetics studies to examine MA/My virus resistance mapped genes to the MHC I D region on chromosome 17 and the NK gene complex (NKC) on chromosome 6. [15][16][17][18] Recently, we identified MHC I D k as a critical genetic factor, 19 and further demonstrated a requisite role of licensed Ly49G2 ϩ NK cells needed in MCMV resistance.…”