Cytomegalovirus MHC class I homologues and natural killer cells: an overview

Microbes and Infection, 2, 2000, 521−532 © 2000 Éditions scientifiques et médicales Elsevier SAS. All rights reserved S1286457900003154/REV

Review

Cytomegalovirus MHC class I homologues and natural killer cells: an overview Helen Farrella*, Mariapia Degli-Espostib, Eloise Densleyb, Erika Cretneyc, Mark Smythc, Nicholas Davis-Poyntera b

a Division of Virology, Animal Health Trust, Kentford, Suffolk, CB8 7UU, UK Department of Microbiology, University of Western Australia, Nedlands, Western Australia, 6907, Australia c Cellular Immunity Laboratory, The Austin Research Institute, Melbourne, Victoria, 3084, Australia

ABSTRACT – Viruses that establish a persistent infection with their host have evolved numerous strategies to evade the immune system. Consequently, they are useful tools to dissect the complex cellular processes that comprise the immune response. Rapid progress has been made in recent years in defining the role of cellular MHC class I molecules in regulating the response of natural killer (NK) cells. Concomitantly, the roles of the MHC class I homologues encoded by human and mouse cytomegaloviruses in evading or subverting NK cell responses has received considerable interest. This review discusses the results from a number of studies that have pursued the biological function of the viral MHC class I homologues. Based on the evidence from these studies, hypotheses for the possible role of these intriguing molecules are presented. © 2000 Éditions scientifiques et médicales Elsevier SAS Cytomegalovirus / immune evasion / MHC class I proteins / NK cells

1. Introduction The herpesvirus family comprises a large group of viruses that have been identified from diverse animal species. Critical to the success of these viruses is their ability to persist lifelong within infected individuals, with infection usually resulting in minimal disease symptoms. This property is consistent with a stable host-parasite relationship, and phylogenetic analysis of herpesvirus genome sequences has supported the hypothesis that these viruses co-evolved with their host species [1]. Further evidence for a highly adapted virus-host relationship has come from the identification of cellular homologues within these virus genomes, indicating that these viruses have usurped normal cellular functions to use to their advantage. A number of these ’hijacked’ gene products are conserved with cellular immune effector cell proteins, highlighting key components of the antiviral immune response [2, 3]. Indeed, the biological impact of virusencoded cellular homologues has been confirmed in several in vivo studies [4–8]. Additional herpesvirus genes implicated in immune subversion/evasion that lack sequence homology with known cellular immune modulators have been identified through functional studies. It is

* Correspondence and reprints. Microbes and Infection 2000, 521-532

likely that the large number of other ’nonessential’ herpesvirus genes to which no function has been ascribed also play a role in virulence, either being novel immune modulators or by affecting tissue tropism in vivo. The cytomegaloviruses (CMVs) are members of the betaherpesvirus subgroup that cause minimal disease in the immunocompetent host. However, individuals with an immature or immunocompromised immune status are at an increased risk of disseminated CMV infection, either through primary infection or reactivation from latency [9]. While the immune system is therefore important in controlling the severity of CMV infection, periods of virus shedding from the immune host have been detected, suggesting that the CMVs possess the capacity to persist and replicate in the face of an active immune response. Furthermore, cells of the macrophage/dendritic lineage provide an important reservoir for persistent and latent CMV infection [10]. These professional antigen-presenting cells provide immunoregulatory signals to the innate and adaptive immune system; it is thus likely that the CMVs have developed mechanisms to thwart the normal antiviral events that initiate in these cells during primary virus infection as well as during reactivation from latency. The impact of these putative viral immune evasion genes on CMV virulence and pathogenesis in the human host is difficult to assess, due to the high species-specificity of the betaherpesviruses. In this regard, the rodent CMVs provide useful experimental systems to assess the contribution of 521

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potential immunomodulatory viral proteins on the virus life cycle in vivo, since both the host and the virus are easily manipulated [11]. An important evasion mechanism involves the modulation of cellular immune-related proteins and in recent years, considerable attention has focussed on the ability of the herpesviruses, in particular the CMVs, to modulate the expression of MHC class I molecules [12, 13]. Cellular MHC class I proteins are expressed on the surface of almost all nucleated cells and play a pivotal role in regulating the immune response to infection by virtue of their role +in the presentation of foreign peptides to cytotoxic CD8 T lymphocytes. The assembly and transport of the tripartite MHC class I/peptide/β2microglobulin (β2m) complex occurs via a complex pathway: each of these three components is translocated across the ER membrane, whereupon the complex precursor is formed [14]. Carbohydrate and conformational modifications to the complex are made as it is transported through the ER lumen and Golgi network; the mature, properly folded complex is presented at the cell surface. At each step of the assembly pathway, cellular chaperones are required for protein stability and translocation [15–17]. Elegant in vitro experimentation has demonstrated that the CMVs interfere at multiple steps with the function of the MHC class 1/β2m/ peptide chaperones [18–23]. While the multiple mechanisms for this interference appear to have evolved independently during the close association of the CMVs with their host species, the prime goal – to inhibit MHC class I-associated antigen presentation – is a common strategy (figure 1). Analysis of murine CMV (MCMV) mutants deleted of m152, a glycoprotein that sequesters cellular MHC class I in the ER, has demonstrated that the virus mutants are cleared from infected animals more rapidly than in a comparable infection with wild type (i.e., m152+) MCMV [24]. Improved clearance was dependent on the presence of CD8+ T cells and provided the first demonstration of the impact of CMV-mediated MHC class I inhibition on viral immune evasion in vivo. The detailed mechanisms of CMV control of cellular MHC class I expression will not be described further here, but are the subject of a number of reviews [24–26]. Another strategy by which the herpesviruses may evade or sabotage the immune response is by the production of virus proteins that mimic the function of cellular immunomodulators. These viral ’decoys’ may either drive an inappropriate immune response or inhibit the normal ’alarm’ signals released by the infected cells. Examples of these are the herpesvirus homologues of chemokines, cytokines, chemokine receptors, Fc receptors, and apoptosis control proteins; these have also been the topic of recent reviews [27–30]. Also included in this group are the homologues of MHC class I molecules that have been identified in the CMVs. This update focuses on the current knowledge and hypotheses concerning the role of the CMV MHC class I homologues in antiviral immunity, in particular the impact on the early defence mechanisms provided by natural killer (NK) cells. Before detailing the mechanisms by which the CMV class I homologues may interfere with immune function, a summary of the recent advances in understanding the functions of MHC class I – 522

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with respect to its receptors and immunoregulatory roles, is provided below.

2. MHC class I proteins and immunity to infection – regulators of NK cell function While the tripartite MHC class I/peptide/β2m complex is required for CD8+ T-cell activation [31], binding of specific MHC class I molecules on NK cells has been shown recently to be inhibitory [32–34]. NK cells appear to use multiple mechanisms to ’sample’ MHC class I expression on target cells. In humans the majority of the NK receptors for MHC class I belong to the immunoglobulin superfamily [35]. The first of these to be identified were designated killer cell immunoglobulin-like receptors (KIRs). They are transmembrane molecules with two or three immunoglobulin domains and resemble receptors for cytokines or growth factors. The discovery of a family of structurally related molecules, the leukocyte immunoglobulin receptors (LIRs) and monocyte immunoglobulin receptors that contain between one and six immunoglobulin-like domains has rapidly extended this family of MHC class I counterstructures [36]. Notably, some of these immunoglobulin-like receptors have also been identified on other cells, including T cells, B cells, basophils, monocyte and dendritic cells for which they also act as functional inhibitors [37–39]. In contrast to the immunoglobulin-like receptors on human NK cells, the predominant MHC class I-binding receptors on murine NK cells (designated Ly49 proteins) are type II transmembrane, C-type lectin-like molecules that are expressed as disulphide-linked homodimers [40]. Genetic mapping analysis has revealed that the Ly49 family members are clustered in the NK gene complex of mouse chromosome 6, for which a syntenic region has been identified on human chromosome 12 [41]. Transgenic expression of Ly49A NK cell receptors has been shown to confer MHC class I specificity and inhibitory function to NK cells, thus confirming the in vivo role of these molecules [42]. Despite the structural dissimilarities between the human KIR and murine Ly49 proteins, both types of receptor are polymorphic, and each NK cell may express several receptors that display different allelic forms. It is possible that the predominance of immunoglobulin-like receptors in humans and lectin-like receptors in mice may reflect the evolutionary changes in human and murine MHC class I molecules. Indeed, the identification of immunoglobulinlike receptors on murine NK cells [43–45] and C-type lectin-like inhibitory heterodimers (CD94/NKG2) on both human [46] and mouse NK cells [47] suggests that both types of receptor existed before the divergence of the species. It is possible that additional receptors remain to be discovered (figure 2). Interestingly, the human and mouse CD94/NKG2 counterstructures are functionally homologous: each has been found to preferentially bind nonclassical class I MHC molecules that are stabilised by peptides derived from class I signal sequences [48–51]. Thus, it has been hypothesised that CD94/NKG2 receptors might be able to detect defects in nonclassical MHC class Microbes and Infection 2000, 521-532

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Figure 1. Steps in the MHC class I presentation pathway that is subverted by CMV. Nascent MHC class I HC is translocated to the ER lumen via the sec61 protein complex. Following translocation, the class I HC is released from sec61, binds β2m (shown as a grey circle) and, stabilised by chaperones, becomes correctly folded and is modified by the addition of carbohydrate. The heterodimer associates with TAP and further chaperones (such as tapasin and calreticulin) to form a ’peptide-loading’ complex. Ubiquitinated peptides are cleaved within the proteasome; trimmed peptides bind to TAP, whereupon they are translocated to the ER lumen in an ATP-dependent process. Binding of peptide to the MHC class I HC/β2m heterodimer confers stability; it is released from TAP and traffics through the ER/Golgi intermediate compartments, then through the cis, medial and trans Golgi compartments to the cell membrane. The CMV genes encoding proteins that interfere with these steps are designated adjacent to the arrows in the pathways. Of the HCMV proteins, the US2, US11, US6 and US3 gene products all act within the ER. US2, and US11 interfere with processing of the nascent class I HC in the ER; US6 prevents peptide translocation across the ER; US3 inhibits the maturation of the heterodimer through the ER. The HCMV UL83 gene product blocks presentation of HCMV proteins at immediate-early times postinfection. Of the MCMV proteins, m152 retains the trimeric complex in the ER-Golgi intermediate, while m06 binds, and redirects the trimeric complex to the lysosomal compartment. The MCMV m04 product (gp34) is unusual in that it is stabilised by binding to the mature MHC class I in the ER, whereupon the gp34/MHC class I complex leaves the ER and is transported to the cell surface. The effect of gp34 on effector molecules that bind MHC class I has yet to be determined. Full description of the mechanism of action of these molecules is the subject of a number of recent reviews [12, 13, 24–26]. Microbes and Infection 2000, 521-532

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Data is emerging concerning the residues critical for interaction between MHC class I molecules and their NK cell receptors. MHC class I exon shuffling experiments and the construction of MHC class I chimeric proteins have shown that the alpha 1 and alpha 2 domains are important for recognition by Ly-49A receptors [54, 55]. In addition, a number of experiments have indicated that murine Ly49 proteins recognise specific MHC class 1 in association with peptide [56–58]; the fact that most classical class I molecules are unstable in the absence of bound peptide suggests that peptide may also be indirectly required for correct MHC class I-Ly49 interaction. Carbohydrate moieties on MHC class I proteins have also been implicated in binding to Ly49 proteins, although the current evidence suggests that it plays a minor, or in some cases, undetectable role in inhibiting NK cytotoxicity [58, 59]. Given the lectin-like properties of the Ly49 molecules, it is possible that they may also bind alternative, and as yet unidentified, ligands. Unlike the Ly49 proteins, the KIR molecules appear to be able to discriminate MHC class I-bound peptide, although recognition of ’empty’ MHC class I proteins has also been reported [60]. Figure 2. Schematic representation of immunoglobulin and C-type lectin receptors of cellular MHC class I and the MHC class I homologues. CD94/NKG2 heterodimers have been identified as receptors for human and murine nonclassical MHC class I molecules. The killer and leucocyte immunoglobulin receptor (KIR/LIR) superfamilies have been identified in man, while the closely related protein family, the paired immunoglobulin-like receptors (PIRs) have been identified in the mouse. The murine C-type lectin Ly49 family has been well characterised in the mouse; a homologous family has not been identified as a human MHC class I receptor. The heavy chain of cellular and viral class I molecules is depicted in black, with closed circles representing the alpha-1, -2 and -3 domains. The partially closed circle for gpm144 represents its truncated alpha-2 domain. The grey circles represents β2m; bound peptide is shown as a horizontal bar. Predicted asparagine-linked glycosylation sites are shown as branching chains extending from the alpha-1, and – 2 domains (murine cellular MHC class I is shown here – human MHC class I lack a conserved glycosylation site on the alpha-2 domain). LIR-1 has been identified as a receptor for gpUL18, although it also binds cellular MHC class I molecules. The counterstructure has yet to be identified for gpm144. I expression (for example, as a result of infection or tumorigenesis) by surveying the cell surface expression of HLA-E or Qa-1b and their associated peptides. Common to all receptors is the nature of the inhibitory signal that is transmitted upon engagement of the MHC class I molecule. Inhibitory receptors possess immunoreceptor tyrosine-based inhibitory motifs (ITIMS) within the cytoplasmic domains of the molecules; these recruit members of the SH2 domain-containing families of tyrosine and inositol phosphatase, which, in turn inhibit signalling through associated activatory receptors [52]. Notably, some receptors with short cytoplasmic domains that lack ITIMS have been shown to activate, rather than inhibit NK cells [53]. 524

4. CMV MHC class I homologues: HCMV UL18 and MCMV m144 HCMV UL18 was the first of the viral MHC class I homologues to be identified [61], and it was initially hypothesised that it participated in the HCMV-mediated inhibition of cellular MHC class I by sequestering β2m. This was based on the high level of amino acid sequence homology between the alpha 3 domain of MHC class I (which interacts with β2m) and UL18. Indeed, while βm sequestration was observed in recombinant vaccinia virusinfected cells expressing high levels of UL18 [62], further experiments confirmed the involvement of HCMV genes other than UL18 in cellular MHC class I inhibition [63]. Subsequent DNA sequence analysis of the mouse and rat CMVs also identified homologues of cellular MHC class I proteins ( [64], Beisser, personal communication). Each of these virus genes is predicted to encode type 1 membrane glycoproteins (gps) with globular domains similar to those of cellular MHC class I heavy chains. While the rodent MHC class I homologues display a high degree of sequence homology, there is little conservation with the human cytomegalovirus MHC class I homologue. Assuming a common ancestral gene, this suggests that they have diverged significantly from a common progenitor CMV genome following segregation of MCMV and HCMV to their respective host species. All possess a predicted asparagine-linked glycosylation site between the first and second globular domains, which is invariant in MHC class I molecules [65]. Despite their homology to MHC class I sequences, it is important to note that the viral class I homologues possess a number of features that are dissimilar to classical class I molecules. Unlike cellular class I, gpUL18 is heavily glycosylated. Although the number of predicted glycosylation sites on gpm144 is similar to that of class I, it lacks the Microbes and Infection 2000, 521-532

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predicted carbohydrate at residue 176 of murine class I, which has been implicated in binding to Ly49 molecules [59]. Both HCMV and MCMV MHC class I homologues have been studied in some detail: these are encoded by the UL18 and m144 genes, respectively, and each has been shown to be nonessential for growth in cell culture [63, 66]. While both gpUL18 and gpm144 bind cellular β2m and are expressed at the surface of transfected cells, only gpUL18 has been shown to bind endogenous peptides [67]. The inability of gpm144 to bind peptide is probably as a consequence of a truncated alpha 2 domain that, in cellular MHC class I, encodes the majority of the peptide-binding cleft [68].

5. Do the CMV MHC class I homologues play a role in evading host NK cell responses? The recognition of the immunoregulatory role of MHC class I on NK cell function inspired renewed interest in the role of UL18 and its rodent CMV counterparts. Considerable data has confirmed the importance of NK cells during the early response to herpesviruses. In humans, longitudinal studies have demonstrated that patients with low or absent endogenous NK cell levels are abnormally susceptible to herpesvirus infections [69]. Evidence for the in vivo protective effect of NK cells against herpesvirus infection has come from studies of MCMV. The efficacy of NK cells in the control of MCMV infection has been shown to correlate with the genetic constitution of the host [70]. Mice deficient in NK cell function as the result of genetic mutation exhibit enhanced morbidity and mortality following MCMV challenge [71–73]. Furthermore, NK cell depletion and reconstitution experiments have demonstrated a protective role for NK cells against MCMV [74, 75]. In addition, genetic analysis of MCMV-susceptible and -resistant mouse strains has led to the identification of the murine Cmv1 gene, which restricts the early replication of MCMV in the spleen through the cytotoxic action of NK cells [76]. The Cmv1 locus maps to the NK gene complex (NKC) on mouse chromosome 6, proximal to the Ly49 family [77]. Given that a syntenic NKC region is located on human chromosome 12, it is possible that a functional homologue of Cmv1 may exist and contribute to the efficacy of the antiviral NK cell response in humans [40]. Since the CMVs possess sophisticated mechanisms to inhibit cellular MHC class I expression, thereby inhibiting the recognition of infected cells by CD8+ cytotoxic T cells in vitro, it was predicted that the same infected cells would be susceptible to attack by NK cells. Accordingly, it has been hypothesised that the combined effect of CMV genes to inhibit cellular MHC class I and express a putative ’decoy’ MHC class I molecule provides a complementary mechanism for these viruses to elude both the innate and adaptive arms of the host immune response. Microbes and Infection 2000, 521-532

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6. Studies of gpul18 in the regulation of NK cytotoxicity Recent studies in support of a role for gpUL18 in directly inhibiting NK cell responses have yielded contrasting results. In vitro analysis of gpUL18-transfected, MHC class I/β2m-deficient, human class I negative 721.221 cells resulted in low, but increased level of cell surface expression of β2m compared with untransfected cells [78]. Stably transfected cells selected for expression of β2m were shown to be resistant to NK cell lysis compared with the parental line. An antibody to the C-type lectin-like receptor CD94 abolished the resistance of transfected cells to NK cell lysis, suggesting that CD94 was the ligand for gpUL18. The identification of CD94 as a candidate lectin-like receptor was consistent with the extensive glycosylation of gpUL18. Notably, however, HLA-E transcripts are detected in 721.221 cells, but the protein is not expressed at the cell surface unless stabilised by the binding of signal sequences from transfected class I molecules, as described above [47–49]. It is possible therefore, that gpUL18 mediated its inhibitory effect against NK cells by upregulating HLA-E cell surface expression rather than via direct interaction with CD94/NKG2A receptors, although the UL18 signal sequence does not conform to the consensus of cellular class I. Using soluble gpUL18 linked to the Fc component of IgG, an alternative receptor for gpUL18 was identified by screening expression libraries derived from several cell lines [36]. This receptor, designated LIR-1 (or ILT2), was the first of the LIR family to be identified; additional proteins closely related to LIR-1 have also been identified [37], but to date, only LIR-1 has been shown to bind to gpUL18, suggesting that a specific biological function of LIR-1 has been targeted by HCMV. LIR-1 also binds cellular MHC class I with broad specificity [79], including the nonclassical HLA-G molecule that is expressed primarily on cells at the maternal-foetal interface [80]. It possesses four extracellular immunoglobulin-like domains and four cytoplasmic ITIMs. Similarly to other inhibitory receptors, the cytoplasmic ITIM of LIR-1 associates with the tyrosine phosphatase, SHP-1. Surprisingly, LIR-1 is expressed on a number of cell types, in particular monocytes, dendritic cells, B cells and a subpopulation of NK cells, suggesting that the interaction of gpUL18 with LIR-1 and its negative regulatory effects extend beyond NK cells [36, 37]. In contrast to the inhibitory effect on NK cells initially reported for gpUL18, a subsequent report has demonstrated that high level, transient expression of gpUL18 in human, primate and rodent cell lines results in enhanced killing by NK cell clones compared with untransfected control cells [81]. In addition, fibroblasts infected with wild-type HCMV and a HCMV mutant deleted of UL18 were killed more efficiently than uninfected controls. No correlation between CD94 expression by the NK cell clones and lysis of HCMV-infected or UL18-transfected cells was detected. Notably, increased sensitivity to NK cell killing in wild-type-infected fibroblasts correlated with the upregulation of the cellular adhesion molecule ICAM-1, and could be blocked by antibodies specific to ICAM-1, demonstrating that ICAM-1 is a critical compo525

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nent in the NK cell-mediated lysis of HCMV-infected fibroblasts. As the LIR-1 status of the NK cell clones was not determined it is possible that ICAM-1 expression induced in HCMV-infected fibroblasts provided an accessory signal to an activating receptor, in the absence of engagement of an inhibitory NK cell receptor by gpUL18. Finally, Fletcher et al. [82] have challenged whether MHC class I inhibition alone by HCMV is sufficient to render infected cells susceptible to NK cell killing. Using fibroblasts infected with different HCMV strains, they demonstrated different susceptibilities to NK cell killing, irrespective of the fact that all strains downregulated class I HLA to a similar extent. Notably, susceptibility to NK cell lysis correlated with upregulation of LFA-3 expression, with virus isolates that downregulated LFA-3 being resistant to NK cell lysis and isolates that upregulated LFA-3 being susceptible. The alteration of LFA-3 levels occurred by an unidentified mechanism at immediate-early/early times postinfection. Interestingly, the sensitivity to NK cell killing in isolates that downregulated LFA-3 was further reduced by the production of an NK cell inhibitor at late times postinfection. These results indicate that the downregulation of MHC class I in some cell types is not sufficient to render them susceptible to NK cell killing and that additional (possibly NK-stimulatory) signals may be required. In this regard, it has become clear that there is considerable variability in the genetic composition of different HCMV isolates and it is possible that genes important for resistance/sensitivity to NK cell killing may be represented in some isolates, and not in others. The apparent contradictory results of the above in vitro studies of gpUL18 reflect the complexity of activating and inhibitory signals which control NK cell function. At the level of the target cell, further understanding of how HCMV infection alters NK stimulatory, as well as inhibitory, molecules is required. It is likely that the density of NK-inhibitory and -activating ligands differs considerably in cells of different lineages and from different tissue compartments. Thus, there is a need to look at the effect of HCMV infection in cells that are representative targets during an in vivo infection. At the level of the NK cell, our understanding of the development of the NK cell receptor repertoire is at its early stages, but it appears that the CD94-NKG2/Ly49/KIR subsets are regulated by different signals, including cytokines such as IL-15 and stromal cell-derived factors [84]. In summary, studies to date have not conclusively demonstrated a direct inhibition of NK cell cytotoxicity by gpUL18. The identification of a gpUL18 receptor distributed on a wide variety of cell types, in particular myeloid cells, suggests that gpUL18 may exert an inhibitory effect that has downstream effects on both innate and adaptive immune responses. With regard to innate immunity, it is therefore possible that gpUL18 can have an indirect effect on NK cytotoxicity, by inhibiting cytokine release by accessory cells important in NK cell activation, in particular, monocytes. Notably, recent studies have demonstrated that murine dendritic cells are potent activators of NK cells in vitro and mediate innate antitumour responses in vivo by a mechanism that is independent of IL-12 or type 1 IFNs [85]. Direct contact between DC and NK cells was required 526

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for NK cell interaction, although the molecular mechanisms involved in the interaction remain to be elucidated. Whether gpUL18-LIR-1 interactions interfere with this activation remains to be determined.

7. Studies of MCMV m144 In contrast to the studies of gpUL18, a functional role for the MCMV counterpart, gpm144 has been demonstrated. We have previously shown that an MCMV mutant deleted of m144 (designated ∆m144) is severely restricted in replication during the first few days following infection compared to wild-type MCMV [66]. In vivo depletion of NK cells restored the virulence of the ∆m144 mutant, demonstrating that gpm144 contributes to immune evasion through interference with NK cell-mediated clearance. Interestingly, mice challenged with ∆m144 develop a significant splenomegaly within the first few days postinfection, suggesting that gpm144 may inhibit the infiltration and/or the proliferation of leucocytes at the site of virus replication. At present, there is no suitable in vitro model for NK cell killing of virus-infected cells that directly correlates with NK cell-dependent clearance of MCMV in vivo. This suggests that NK cell-mediated cytolysis is either directed against cell types that have not yet been tested in vitro, or that gpm144 interferes with the cytokine regulation of NK cells or the cytokine-mediated virus clearance mechanisms. Nevertheless, a partial inhibitory effect of gpm144 on NK cytotoxicity in vitro has been demonstrated by Kubota et al., who investigated the susceptibility of a number of murine, rat and human cell lines transfected with gpm144 [86]. Only the Burkitt lymphoma line, Raji, expressed a significant level of gpm144 on the cell surface. The gpm144 was found to be associated with β2m and partially inhibited antibody-dependent cell-mediated cytotoxicity of IL-2-activated mouse NK cells. Interestingly, antibodies against the known murine NK inhibitory receptors, Ly49A, C, G and I, did not affect the inhibitory effect of gpm144, suggesting that gpm144 inhibits NK cells by interacting with a novel receptor. Our studies employing a peritoneal model of tumour rejection [87] have confirmed that gpm144 also has a direct inhibitory effect on IL-2-activated NK cells. Previous studies have demonstrated that perforin-dependent NK cell cytotoxicity is the major mechanism by which tumours with low or variant class I expression are rejected in the mouse peritoneum. In this model, tumour necrosis factor (TNF) is critical for NK-mediated tumour rejection in the peritoneum, but not at other sites, suggesting that the local microenvironment may provide specialised signals to regulate NK cell effector function [88]. RMA-S tumour cells (which, due to a deficiency in the TAP-2 peptide transporter, possess negligible levels of endogenous cell surface MHC class I and are thus highly susceptible to NK cell cytotoxicity) expressing gpm144 conferred modest, but significant resistance to lysis by bulk IL-2-activated NK cells [88]. Interestingly, gpm144 did not confer resistance to killing by resting NK cells, suggesting that a receptor for gpm144 may be induced on activated NK cells. Of imporMicrobes and Infection 2000, 521-532

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tance however, was the ability of gpm144 to protect RMA-S cells from NK cell-mediated clearance in vivo, demonstrating that gpm144, in the absence of other MCMV proteins, is able to inhibit the NK cell response, resulting in an increased tumour load. In contrast to control animals, RMA-S-gpm144 challenged mice failed to develop a marked NK1.1+ cellular infiltrate to the peritoneum, suggesting that gpm144 may inhibit the normal stimulatory signals that promote leucocyte infiltration, and, possibly, activation, in response to tumour challenge. The role of the cellular microenvironment in regulating the NK cell response has also been addressed by Tay and Welsh [89], who demonstrated different mechanisms by which NK cells clear MCMV infection in the liver and spleen. While NK cell-activatory cytokines have been shown to play an important antiviral role in the liver, the cytotoxic mechanism itself is critical for MCMV clearance from the spleen. Recent studies in our laboratory have indicated that in the livers, but not the spleens of MCMVinfected mice, the ∆m144 mutant is cleared more rapidly than wild-type virus in an NK cell-dependent manner that is also dependent on IL-12 and IFN-γ [90]. Taken together, our studies with gpm144 using peritoneal tumour model and experimental MCMV model suggest that gpm144 may inhibit NK cell function by more than one mechanism. In addition to direct inhibition of cytotoxicity, other mechanisms include the interference of gpm144 with NK cell ’accessory cells’ that produce cytokines (e.g., IL-12, IL-15) and/or chemokines (e.g., MIP-1α), that are important for NK cell trafficking and activation [91]. In addition, gpm144 on virus-infected cells may interfere with cellular or cytokine interactions that are important for increased NK cell cytolytic activity, as described above. Clearly, the identification of the counter-receptor for gpm144 will enable these mechanisms to be elucidated.

8. Summary Studies of the CMV MHC class I molecules has revealed new and intriguing insights into the regulation of NK immunity. While the evidence to date has not demonstrated a functional role for gpUL18 in NK-mediated antiviral immunity, it is important to note that the inhibitory role of its counterpart, gpm144, on NK cells has come largely from in vivo experimentation which cannot be duplicated for HCMV. Evidence is accumulating for both gpUL18 and gpm144 that these proteins may exert their inhibitory effects by more than one mechanism. Indeed, it is possible that they possess more than one function, which has been demonstrated for a number of herpesvirus proteins. Possible mechanisms of action of gpUL18 and gpm144 on NK activity are outlined below; they are not mutually exclusive and have yet to be formally proven, particularly in the context of a virus infection. Direct inhibition of NK cell cytotoxicity via interaction with an inhibitory counterstructure on NK cells (figure 1A, B). At present, there is no evidence that HCMV gpUL18 confers protection to virus-infected cells through the interaction with its known receptor, LIR-1 on NK cells. Although LIR-1 is found on a wide range of cells, it has been Microbes and Infection 2000, 521-532

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detected on only a small subset of NK cells. While it is possible that a small subpopulation of LIR-1+ NK cells are critical in vivo for HCMV clearance, the fact that LIR-1 is expressed on such a broad range of cell types suggests that gpUL18 may inhibit a number of alternative pathways. It is also possible that an alternative NK receptor may exist (or be induced during HCMV infection) that directly interacts with gpUL18 on infected cells in vivo. For gpm144, there is now considerable evidence that it has the capacity to inhibit the cytotoxic function of NK cells from bulk cultures, although the nature of the counterstructure is still unknown. It should be noted however, that it remains to be determined whether the direct inhibition of NK cytotoxicity by gpm144 occurs in MCMV-infected cells. Indirect inhibition of NK cell function via engagement of inhibitory receptors on NK ’accessory’ cells such as monocytes, macrophages and/or dendritic cells (figure 2A, B). Interaction with the CMV MHC class I homologues may inhibit key cytokines required for NK cell recruitment and activation. Given the wide cellular distribution of ITIM+ MHC class I receptors, it is likely that cells in addition to NK cells receive inhibitory signals upon binding to cell surface MHC class I proteins, and that, in the absence of MHC class I, the inhibitory effect of class I is relinquished. The consequence of the inhibitory signals may affect the release of cytokines that activate NK cells. The broad distribution of LIR-1 on cells of the myeloid lineage is consistent with the notion that, for HCMVinfected cells, gpUL18-LIR-1 interactions invoke an inhibitory response in a variety of cell types, although the effect of the interaction on these cells remains to be elucidated. For MCMV, in vivo studies comparing ∆m144 and wildtype MCMV infections have indicated that ∆m144 is significantly more efficient in the early recruitment of cells to the site of virus infection. Furthermore, cytokinemediated mechanisms have been shown to be an important component of ∆m144 clearance from the liver, but not the spleen, of infected animals. In addition, recruitment of cytotoxic NK cells to the peritoneum by gpm144transfected RMA-S tumour cells was significantly lower compared with untransfected RMA-S tumour cells. These cytokine-mediated mechanisms may be of particular importance during CMV persistence and reactivation from latency, stages of infection which are characterised by relatively few cells undergoing a lytic infection. Indirect inhibition of NK cell functions via expression of the MHC class I homologues in NK accessory cells (figure 3A, B). Cells of the monocyte/macrophage lineage are also key targets for CMV infection in vivo, and in these circumstances, the CMV class I homologues may inhibit their accessory function, by cis-binding to cognate inhibitory receptors via extracellular domains, or by novel intracellular interactions which block or inhibit the stimulatory signals. Alternatively, in the case of LIR-1, which binds both gpUL18 and cellular class I molecules, cis-binding mechanisms may mask the normal negative regulatory effects of LIR-1, resulting in an intracellular environment that promotes HCMV replication, as proposed by Cosman et al. [92]. For MCMV gpm144, our results with gpm144transfected RMA-S cells demonstrate an inhibitory effect on NK cell cytotoxicity via a trans-binding interaction. 527

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Figure 3. Schematic representations of the effect of CMV infection on NK cell cytotoxicity and recruitment in the presence of either gpm144 or gpUL18 expression (1A, 2A, 3A) or in their absence (1B, 2B, 3B). 1 A,B. The viral class I homologues (v) expressed on the surface of infected cells (IC) may send an inhibitory signal to NK cells, thus preventing cytolysis; in the absence of gpm144/gpUL18, the CMV-induced downregulation of cellular MHC class I molecules (M) would lead to the activation of the NK cell-mediated cytolytic pathway. 2 A,B. CMV-infected cells may stimulate NK accessory cells via the release of NK cell stimulatory cytokines; a signal which may be inhibited by the viral class I homologues. 3 A,B. Cis-binding of the viral MHC class I molecules with its receptor may lead to inhibition of NK cell stimulatory cytokines, preventing NK cell recruitment and activation. 528

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CMV MHC class I homologues and NK cell immunity

Nevertheless, it remains to be determined if, in the context of an infected accessory cell, gpm144 and gpUL18 interact with molecules that have downstream effects on NK cell function. It is now almost 25 years since the role of MHC class I in shaping the adaptive immune response was discovered [93]. In the past decade, we have seen a new role for MHC class I molecules in innate immunity, and the emergence of novel, nonclassical MHC class I proteins which also have immunoregulatory roles on NK cells. As both roles have significant impacts on immunity to virus infections, it is perhaps not surprising that persistent viruses have evolved sophisticated strategies to circumvent the immunomodulatory activities of MHC class I. When developing models for the functions of viral proteins interacting with MHC class I, it will be important to consider cell types in addition to CD8+ CTLs, such as NK cells, monocytes, dendritic cells and other lymphocytes. These viruses and natural models of virus infection are thus valuable tools in elucidating the key components of immunological pathways.

Acknowledgments The authors acknowledge P. Beisser and C. Vink for permission to include unpublished data. HF is supported by the Animal Health Trust, and the Biotechnology and Biological Sciences Research Council (BBSRC). EC and MD-E are supported by grants from the National Health and Medical Research Council of Australia (NH & MRC). MS is supported by a fellowship from the NHMRC. ND-P is supported by a Tetra Laval Fellowship.

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