MHC Class I regulated virus immunity: Licensed NK cells enhance CD8T cell viral immunity

NK cells play an essential role in immunity to MCMV infection. We have shown that NK cell-mediated MCMV resistance is under MHC-I Dk control in MA/My mice, yet whether non-MHC genes modify this resistance is unknown. Furthermore, while the impact of NK-mediated MCMV control on dendritic cells and adaptive immunity has been extensively studied in C57BL/6 mice, whether NK-mediated virus control directed by MHC-I polymorphism affects virus-specific adaptive immunity is unknown. MHC-I Dk resistance varies with genetic background, and using a classical genetics approach we identified modifiers of virus resistance. Examining spleen and liver MCMV levels and genome-wide genotypes in F2 offspring between MA/My (H-2k) and C57L (H- 2b), we identified quantitative trait loci on chromosomes 6 and 19 which contribute to virus control independent of H-2k. The chromosome 6 QTL was linked with the NK gene complex and we show that this QTL provides MCMV control independent of H-2k via NK cells.

Since we have defined a role for Ly49G2+ NK cells and MHC-I Dk in MCMV resistance, we examined whether MHC-I-regulated MCMV control influenced dendritic cells and virus-specific virus immunity. We demonstrate that MHC-I Dk and Ly49G2+ NK cells were required for the recovery of conventional dendritic cells (cDC) and robust expansion of virus-specific effector CD8 T cells following MCMV infection. Ly49G2 NK cell depleted mice, as well as mice without MHC-I Dk, failed to recover splenic cDCs after infection; consequently effector CD8 T cells were significantly reduced and virus6 specific T cell immunity was severely impaired. Thus, NK inhibitory receptor recognition of MCMV infection apparently led to qualitative changes in CD8a DCs needed to prime CD8+ T cells. While MHC Class I is essential to NK cell effector and surveillance functions, we have identified MHC-I independent virus control loci, revealed the first in vivo role for an NK inhibitory receptor in MCMV control, and illustrated how MHC-I polymorphism directs adaptive immunity through NK cells.