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 Ly49G2 (G2) inhibitory receptor-expressing NK cells are essential to murine CMV (MCMV) resistance in MA/My mice. Without D(k), G2(+) NK cells in C57L mice fail to protect against MCMV infection. As a cognate ligand of G2, D(k) licenses G2(+) NK cells for effector activity. These data suggested that D(k)-licensed G2(+) 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 G2 expression on naive blood NK cells was predictive of MCMV resistance. However, rapid G2(+) 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 G2(+) 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.
Division of Nephrology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908;
Jessica
J
Prince
Alyssa
A
Lundgren
Michael D
MD
Stadnisky
William T
WT
Nash
Amira
A
Beeber
Stephen D
SD
Turner
Michael G
MG
Brown
D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D005805:Genes, MHC Class I / Q000235:genetics; D005838:Genotype; D006566:Herpesviridae Infections / Q000276:immunology* / Q000821:virology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018146:Muromegalovirus / Q000276:immunology*; D055650:NK Cell Lectin-Like Receptor Subfamily A / Q000378:metabolism; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000378:metabolism
D000950:Antigens, Ly; D015395:Histocompatibility Antigens Class I; C527095:Klra7 protein, mouse; D055650:NK Cell Lectin-Like Receptor Subfamily A; D055627:Natural Cytotoxicity Triggering Receptor 1; C118384:Ncr1 protein, mouse