Deficient major histocompatibility complex-linked innate murine cytomegalovirus immunity in MA/My.L-H2(b) mice and viral downregulation of H-2(k) class I proteins

NK cells are key effectors of innate immunity and host survival during cytomegalovirus (CMV) infection. Innate marine CMV (MCMV) resistance in MA/My mice requires Ly49H/m][57-independent H-2(k)-linked NK cell control. Here we show that replacement of MA/My H-2(k) with C57L H-2(b) susceptibility genes led to a remarkable loss of innate virus immunity, though NK gamma interferon was induced in H-2(b) and H-2(k) strains shortly after infection. Thus, H-2(b) genes expressed in C57L or MA/My.L-H2(b) 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-2(k)-linked MCMV resistance. Importantly, this analysis excluded the gene interval from K-k class I through class II. The responsible gene(s) therefore resides in an interval spanning D-k class la and more-distal major histocompatibility complex (MHC) nonclassical class Ib genes. Recently, the NK activation receptor Ly49P and MHC class I D-k proteins were genetically implicated in MCW resistance, in part because Ly49P-expressing reporter T cells could specifically bind D-k molecules on MCMV-infected mouse embryonic fibroblasts (MEFs). However, as we found that H-2(k) innate resistance differs in the C57L or MA/My backgrounds and because NICNIV very efficiently downregulates H-2(k) class I proteins in L929 cells and primary MEFs shortly after infection, a Ly49P/D-k model should not fully explain H-2(k)-linked NICNIV resistance.