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

Abstract

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 (H2 (k)) 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 H2 (k) 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.

Ly49 cluster sequence analysis in a mouse model of diabetes: an expanded repertoire of activating receptors in the NOD genome

“…39 Similarly, Ly49P provides resistance to MCMV infection in MA/My mice although the mechanism is distinct from Ly49H. 31 The current study reveals that NOD mice may have up to four functional anti-MCMV activating Ly49 (Ly49h, u, p 1 and p 3 ). Thus, NOD, like B6 and MA/My, may be resistant to MCMV.…”

“…MCMV plaque assay was performed as described previously. 31 BALB/c MEF used for plaque assays were a kind gift of Dr. Silvia Vidal (McGill University, Montréal, QC, Canada).…”

“…The NOD haplotype has seven Ly49 genes that are predicted to produce functional activating receptors: Ly49h, m, w, p 1 , p 3 , u and d. The Ly49h, p 1 and u genes are newly identified in the current study and their surface expression needs to be confirmed by the production of specific monoclonal antibodies. Like Ly49H, Ly49P has been implicated in the resistance of MA/My mice to murine cytomegalovirus (MCMV), 31 thus, the finding of three Ly49p-related genes in one haplotype is especially intriguing. The close identity between the functional Ly49p 1 , p 3 , and the pseudogene Ly49p 2 cDNAs (and previously identified Ly49p alleles) is shown in Figure 2b.…”

“…In contrast to Ly49H, Ly49P recognizes MCMVinfected cells in the context of H-2D k . 31 Thus, it is not surprising that Ly49P has some affinity for MHC of noninfected cells. As the Ly49D subfamily is closely related to Ly49P (Figure 3), it is logical that Ly49D also has affinity for normal MHC.…”

Identification of bidirectional promoters in the human KIR genes

“…1 In contrast to cytotoxic T lymphocytes that require class I MHC for target recognition, NK cells kill target cells that have altered or absent class I, owing to NK cell expression of inhibitory receptors for normal host class I as well as activating receptors that recognize abnormal class I or mimics of class I generated by viruses. 2,3 The class I MHC receptors expressed by human and murine NK cells belong to distinct protein families; the human killer Ig-like receptor (KIR) proteins are members of the immunoglobulin superfamily, 4 and the murine Ly49 proteins are related to the C-type lectins. 5 Consistent with the analogous functional role of these receptor families, they share similar signal transduction pathways, and the gene clusters encoding the receptors possess extreme allelic variation as well as differences in gene content between individuals.…”