Viral MHC Class I–like Molecule Allows Evasion of NK Cell Effector Responses In Vivo

Abstract

The outcome of mouse CMV (MCMV) infection varies among different inbred mouse strains depending on NK cell effector functions governed through recognition receptor triggering. NK cells from different mouse strains possess diverse repertoires of activating or inhibitory Ly49 receptors, which share some of their polymorphic MHC class I (MHC-I) ligands. By examining the NK cell response to MCMV infection in novel BALB substrains congenic for different MHC (or H-2 in mice) haplotypes, we show that recognition of viral MHC-I–like protein m157 by inhibitory Ly49C receptor allows escape from NK cell control of viral replication. Dominant inhibition by Ly49C bound to self–H-2b encoded MHC-I molecules masks this effect, which only becomes apparent in distinct H-2 haplotypes, such as H-2f. The recognition of m157-expressing cells by Ly49C resulted in both decreased NK cell killing in vitro and reduced rejection in vivo. Further, control of infection with m157-deletant (Δm157) MCMV was improved in mice carrying H-2 molecules unrecognized by Ly49C but allowing expansion of NK cell effectors expressing activating Ly49L receptors. Hence, our study is the first, to our knowledge, to demonstrate that MHC-I mimicry strategies used by MCMV to avoid NK cell control are biologically relevant during in vivo viral infection. Of value for human studies is that only a few genetic assortments conditional on the repertoires of viral MHC-I–like proteins/host NK receptors/MHC haplotypes should allow efficient protection against CMV infection.

Cell-Derived Viral Genes Evolve under Stronger Purifying Selection in Rhadinoviruses

“…A counterstrategy employed by viruses is the downregulation of host MHC molecules to avoid detection by T cells, but this leaves the infected cell vulnerable to lysis by natural killer (NK) cells responding to changes in MHC presentation. It is therefore plausible that CrHV2 captured an MHC homolog to disguise infected cells by using a decoy MHC molecule, a strategy that has been demonstrated for other viruses (42,43). In this context, the increased purifying selection may act to preserve the recognition of the decoy by NK cells.…”

Major histocompatibility complex class I-restricted protection against murine cytomegalovirus requires missing-self recognition by the natural killer cell inhibitory Ly49 receptors

“…Indeed, 264 MCMV-encoded m157 can engage Ly49 inhibitory receptors in mouse strains that do not have Ly49H 265 activation receptor-equivalents; e.g. Ly49I in 129 mice [15] and Ly49C in BALB/c [20]. We predict that 266 m157 inhibition of NK cell function will depend on whether these inhibitory receptors are in hosts with 267 appropriate MHC-I alleles for licensing.…”

“…We predict that 266 m157 inhibition of NK cell function will depend on whether these inhibitory receptors are in hosts with 267 appropriate MHC-I alleles for licensing. Indeed, m157 effects on inhibiting NK cell control appear to be 268 MHC-dependent [20], suggesting such potential interactions. Moreover, MCMV has 11 ORFs with 269 predicted MHC-I folds [38], some of which have been verified by crystallographic studies, and thus may 270 be similarly involved in modulating NK cells.…”

“…60 61 Indeed, prior studies suggested that licensed NK cells hamper MCMV control through inhibitory 62 receptors for host MHC-I [18]. However, other studies suggest that inhibitory Ly49s may enhance MCMV 63 control, but these approaches have utilized mouse strains with poorly characterized Ly49s and Ly49 64 depleting antibodies with unclear specificities and that also affect total NK cell number, confounding 65 interpretations [16,19,20]. Thus, the in vivo role of licensed NK cells and inhibitory Ly49s in viral 66 infections is incompletely understood.…”

NK cell interplay with cytomegaloviruses

“…A portion of Ly49H+ NK cells remain as long lived cells with properties in some way analogous to memory T-cells (Box 1). Recently, it was shown that m157 variant from G1F and Smith strain MCMV can also engage inhibitory Ly49C [78,79] (d). (f) NK cells co-expressing Ly49H and C show diminished effector functions against target cells infected with G1F virus [78].…”