Selective Down-Regulation of the NKG2D Ligand H60 by Mouse Cytomegalovirus m155 Glycoprotein

Abstract

Natural killer (NK) cells are an important defense mechanism against pathogens, particularly against viruses belonging to the herpesvirus family (45, 48). NK cell receptor genes do not undergo somatic recombination and clonal specification (38), and their activation is tightly regulated by a balance of signaling through inhibitory receptors specific for major histocompatibility complex (MHC) class I proteins and activating NK cell receptors with diverse specificities (28). Some activating NK receptors are specific for viral proteins, such as the m157 protein of murine cytomegalovirus (MCMV) and the hemagglutinins of Sendai virus and influenza virus, which are recognized by Ly49H, NKp44, and NKp46, respectively (4,5,31,46). NKG2D is a type II C-lectin-like activating NK cell receptor that was first identified as a member of the NKG2 family (21) and is expressed on all NK cells, as well as on CD8ϩ T cells, ␥␦ T cells, and macrophages (6,15,17,22). NKG2D is a promiscuous receptor that can recognize a broad spectrum of cell surface ligands that are distantly related to MHC class I molecules and are up-regulated on stressed, infected, or transformed cells (11). The known NKG2D ligands on human cells are the MHC class I chain-related molecules (MICA and MICB) (6, 47) and the UL-16 binding proteins (ULBP-1, ULBP-2, and ULBP-3) (12), whereas the mouse NKG2D ligands are H60 (15, 30), retinoic acid early inducible gene 1 (RAE-1␣, -␤, -␥, -␦, and -ε isoforms) (10), and the recently identified murine UL-16 binding protein-like transcript 1 (MULT-1) (9). H60 was originally described as a minor histocompatibility antigen recognized by T cells from C57BL/6 mice in response to BALB.B splenocytes (30), and RAE-1 has been shown to play a role during embryonic development (57).Cytomegaloviruses (CMVs) possess a remarkable range of mechanisms to escape or subvert the immune response (2). Both human CMV (HCMV) and MCMV have developed mechanisms for evading the control of NK cells by interfering with the expression of NKG2D ligands (36). The HCMV protein encoded by the UL16 gene binds ULBP-1, ULBP-2, and MICB (12), preventing these ligands from being expressed on the surfaces of HCMV-infected cells (16,55). Based on their early susceptibility to MCMV infection, mouse strains can be either resistant or sensitive to this virus (18,43). In resistant mouse strains, NK cells become activated via an interaction of Ly49H, an activating NK cell receptor, with the MCMV-encoded m157 protein (3,46). In contrast, Ly49H-negative mouse strains, including most wild mice, show very low NK activities against MCMV, rendering them susceptible to this virus (42). The puzzling fact that Ly49H-negative mice, although being capable of mounting an effective NK cell response against other pathogens (54), are unable to create effective NK cell control of MCMV, has recently been explained by the MCMV-driven down-regulation of cellular ligands for the NKG2D receptor (27). MCMV gp40, a viral glycoprotein encoded by the m152 gene, apart from down-regulating MHC c...

Liver-specific HBsAg transgenic mice are over-sensitive to Poly(I:C)-induced liver injury in NK cell- and IFN-γ-dependent manner

“…Until now, no report including our preliminary study (data not shown) demonstrates that HBsAg has the character. Also, virus proteins such as MCMV m155-, m145-, m152-or m138-encoded glycoprotein may induce the virus infected cells to down-express or upexpress the ligands of activating NK cell receptor (so called ''induced-self'' or ''missing-self'', respectively), by which NK cells may attack self-tissue too [34][35][36][37][38]. We practiced the experiments to explore the ligands of activating NK cell receptor on hepatocytes of HBsAg transgenic mice, and no significant change was found (data not shown).…”

Human Cytomegalovirus Encodes an MHC Class I-Like Molecule (UL142) That Functions to Inhibit NK Cell Lysis

“…However, 11 other ORFs in MCMV were also shown to have MHC-like folds and to be transmembrane glycoproteins (26). Three of these, m145, m152, and m155 have subsequently been shown to sequester stress-induced molecules (MULT1, RAE1, and H60, respectively) that would normally engage the NKG2D-activating NK receptors and interfere with NK cell activation and virus control (27)(28)(29)(30). UL16 of HCMV is known to sequester only some of the human ligands for NKG2D: it does not affect MICA or ULBP3.…”

“…Subsequent investigations have shown that three other ORFs which had been identified as having MHC-like folds in MCMV, m145 and m155, were able to mediate NK evasion, as these molecules sequestered cellular ligands that would bind the activating NK receptor NKG2D (27)(28)(29)(30).…”

Murine cytomegalovirus regulation of NKG2D ligands

“…The mutant virus lacking the m155 gene was also sensitive to NK cell control in vivo, due to its inability to downregulate the NKG2D ligand H60 [50]. We have demonstrated that m155 is able to aVect H60 in isolated conditions, without the involvement of other MCMV proteins.…”

“…In turn, MCMV regulates the NKG2D ligands MULT-1, RAE-1 and H60 through the m145, m152 and m155 proteins, respectively (Fig. 1b) [48][49][50][51][52]. Furthermore, the deletion of either of MCMV genes encoding inhibitors of NKG2D ligands resulted in rescuing the expression of their target ligand and an enhanced sensitivity of mutant viruses to NK cell control in vivo (Fig.…”