MHC class I polymorphism defines NK cell-mediated resistance to murine cytomegalovirus

Abstract NK cells are vital to innate antiviral defenses; NK deficiency corresponds to susceptibility to infection, inflammation, tissue damage, and mortality. In MA/My mice, NK-mediated resistance to murine (M)CMV infection requires H-2k, but a critical gene has not been identified. We mapped the resistance effect to the MHC class I (MHC-I) D locus. A cloned Dk transgene was microinjected into MCMV-susceptible (MA/My.L-H2b x C57L)F1 embryos. MHC-I Dk founders were backcrossed to MA/My.L-H2b or C57L mice. We found that transgenic MHC-I Dk expression conferred MCMV resistance. Ly49G+ NK cells were required since their removal before infection abrogated resistance. Using bone marrow chimeras, a requirement for MHC-I Dk expression in hematopoietic or non-hematopoietic cells was found essential to full MCMV resistance. MHC-I Dk resistance through Ly49G+ NK cells further corresponded to splenic CD11c+ dendritic cell stability and acquisition of virus-specific CD8+ T cells after infection. We conclude that MHC-I Dk is essential to MCMV resistance and define a role for MHC-I Dk on both hematopoietic and non-hematopoietic cells in enhancing NK virus control and virus-specific immunity.