Multiparametric Analysis of Host Response to Murine Cytomegalovirus in MHC Class I–Disparate Mice Reveals Primacy of Dk-Licensed Ly49G2+ NK Cells in Viral Control

MHC class I D k and Ly49G 2 (G 2 ) inhibitory receptor–expressing NK cells are essential to murine CMV (MCMV) resistance in MA/My mice. Without D k , G 2 + NK cells in C57L mice fail to protect against MCMV infection. As a cognate ligand of G 2 , D k licenses G 2 + NK cells for effector activity. These data suggested that D k -licensed G 2 + NK cells might recognize and control MCMV infection. However, a role for licensed NK cells in viral immunity is uncertain. We combined classical genetics with flow cytometry to visualize the host response to MCMV. Immune cells collected from individuals of a diverse cohort of MA/My × C57L offspring segregating D k were examined before infection and postinfection, including Ly49 + NK subsets, receptor expression features, and other phenotypic traits. To identify critical NK cell features, automated analysis of 110 traits was performed in R using the Pearson correlation, followed with a Bonferroni correction for multiple tests. Hierarchical clustering of trait associations and principal component analyses were used to discern shared immune response and genetic relationships. The results demonstrate that G 2 expression on naive blood NK cells was predictive of MCMV resistance. However, rapid G 2 + NK cell expansion following viral exposure occurred selectively in D k offspring; this response was more highly correlated with MCMV control than all other immune cell features. We infer that D k -licensed G 2 + NK cells efficiently detected missing-self MHC cues on viral targets, which elicited cellular expansion and target cell killing. Therefore, MHC polymorphism regulates licensing and detection of viral targets by distinct subsets of NK cells required in innate viral control.