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

Abstract

MHC I Dk and Ly49G2 inhibitory receptor-expressing NK cells are essential to murine (M)CMV5 resistance in MA/My mice. Without Dk, Ly49G2+ NK cells in C57L mice fail to protect against MCMV infection. As a cognate ligand of Ly49G2, Dk licenses Ly49G2+ NK cells for effector activity. These data suggested that Dk-licensed Ly49G2+ 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/MyxC57L offspring segregating Dk were examined before and after infection, 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 Pearson’s 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 Ly49G2 expression on naïve blood NK cells was predictive of MCMV resistance. However, rapid Ly49G2+ NK cell expansion following viral exposure selectively occurred in Dk offspring; this response was more highly correlated to MCMV control than all other immune cell features. We infer that Dk-licensed Ly49G2+ NK cells efficiently detected missing-self MHC cues on viral targets, which elicited cellular expansion and target cell killing. MHC polymorphism therefore regulates licensing and detection of viral targets by distinct subsets of NK cells required in innate viral control.

Impaired NK‐cell education diminishes resistance to murine CMV infection

“…Our results delineate that self‐MHC D k expression in both hematopoietic and nonhematopoietic cells was required to adequately license G2 + NK cells, while lineage‐restriction of the self‐ligand resulted in impaired NK‐cell functionality and less effective viral clearance. The findings are in agreement with previous reports that linked G2 + NK cells with MCMV resistance and selective expansion after MCMV exposure in mice with self‐MHC D k . The current study firmly establishes that NK cells reconstituted after allogeneic BM transplantation had increased reactivity due to self‐MHC education, which directly corresponded to more effective NK‐mediated virus resistance.…”

Genomic Modifiers of Natural Killer Cells, Immune Responsiveness and Lymphoid Tissue Remodeling Together Increase Host Resistance to Viral Infection

“…Previously we assessed the immune response to MCMV with a deep phenomic approach [ 23 ]. The original high dose (HD) cohort [ 23 ] and a second cohort of MA/My x C57L hybrid mice given lower dose (LD) infection are included in the current analysis ( S1 Fig ). All mouse genome-wide genotypes were assessed and verified using automated SNP analysis on an Illumina platform.…”

Know Thyself: NK-Cell Inhibitory Receptors Prompt Self-Tolerance, Education, and Viral Control

“…This question was further tested in a large-scale genetic analysis of the host response to MCMV (124). More than 200 mice disparate for the G2 c57l cognate-ligand, D k , were analyzed for immune and NK-cell features in the response to infection, in parallel with viral control.…”