MHC Class I regulated virus immunity: Licensed NK cells enhance CD8T cell viral immunity
Stadnisky, Michael David, Department of Microbiology, University of Virginia
Brown, Michael, Department of Microbiology, University of Virginia
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.
PHD (Doctor of Philosophy)
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