Epistasis between mouse Klra and major histocompatibility complex class I loci is associated with a new mechanism of natural killer cell-mediated innate resistance to cytomegalovirus infection

Experimental infection with mouse cytomegalovirus ( MCMV) has been used to elucidate the intricate host-pathogen mechanisms that determine innate resistance to infection. Linkage analyses in F-2 progeny from MCMV-resistant MA/My (H2(k)) and MCMV-susceptible BALB/c (H2(d)) and BALB. K ( H2k) mouse strains indicated that only the combination of alleles encoded by a gene in the Klra ( also called Ly49) cluster on chromosome 6, and one in the major histocompatibility complex (H2) on chromosome 17, is associated with virus resistance. We found that natural killer cell - activating receptor Ly49P specifically recognized MCMV-infected cells, dependent on the presence of the H2k haplotype. This binding was blocked using antibodies to H-2D(k) but not antibodies to H-2K(k). These results are suggestive of a new natural killer cell mechanism implicated in MCMV resistance, which depends on the functional interaction of the Ly49P receptor and the major histocompatibility complex class I molecule H-2D(k) on MCMV-infected cells.