IntroductionHuman cytomegalovirus (HCMV) infection generally follows a subclinical course, but may lead to severe disorders in immunocompromised individuals and is a main cause of infectious congenital diseases. HCMV remains latent in immunocompetent hosts, undergoing occasional reactivation. 1 Studies in murine models revealed that an effective defense against CMV requires the participation of natural killer (NK) and T cells. 2,3 Detection of antibodies and CD8 ϩ T lymphocytes specific for HCMV antigens allow an assessment of the adaptive immune response to the pathogen. 4,5 To escape from CD8 ϩ T cells, HCMV inhibits the expression of human leukocyte antigen (HLA) class I molecules and interferes with antigen presentation using a set of glycoproteins (US2, US3, US6, US10, and US11) whose genes are clustered within the unique short (US) region of the virus genome. [6][7][8] The loss of HLA class I molecules in HCMV-infected cells impairs the engagement of inhibitory receptors and prompts the activation of NK cell effector functions; reciprocally, the virus has developed several strategies to evade NK-mediated recognition. 9 The nature of receptor-ligand interactions involved in the NK cell response to CMV-infected cells is incompletely understood. In strains of mice expressing the Ly49H receptor, NK cell functions are triggered upon recognition of the m157 mouse CMV (MCMV) glycoprotein, becoming essential to control replication; 10,11 by contrast, human activating NK cell receptors (NKRs) specific for HCMV molecules have not been identified. The involvement of activating killer immunoglobulin (Ig)-like receptors (KIRs) and natural cytotoxicity receptors (NCRs; ie, NKp46, NKp30, and NKp44) in the response to HCMV is uncertain. The interaction of the pp65 HCMV tegument protein with NKp30 has been reported to inhibit rather than to activate NK cell functions. 12 The ability of the UL16 HCMV molecule to interfere with the surface expression of NKG2D ligands, [13][14][15] and the evidence that similar evasion mechanisms operate in MCMV infection, 16,17 support an important role for this killer lectinlike receptor (KLR) in the antiviral defense. 18 Recently, the UL141 HCMV molecule has been shown to inhibit the expression in infected cells of CD155, a ligand for the DNAM-1 stimulating receptor. 19 HCMV may also escape NK-mediated surveillance by keeping inhibitory receptors for HLA class I molecules engaged. The viral UL18 molecule binds with high affinity to the ILT2 (CD85j) inhibitory receptor, 20,21 though its role in immune evasion has not been precisely elucidated. 9 On the other hand, HLA-E appears constitutively resistant to the action of US2 and US11, 22 and it also becomes refractory to the action of US6 when bound to a peptide from the leader sequence of the HCMV UL40 protein. 23 For personal use only. on May 10, 2018. by guest www.bloodjournal.org From interfere with the NK cell response by engaging the inhibitory CD94/NKG2A KLR. 25 We recently reported 26 that healthy HCMV-seropositive individuals display...

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Members of the α- and β-subfamily of herpesviridae encode glycoproteins that specifically bind to the Fc part of immunoglobulin (Ig)G. Plasma membrane resident herpesviral Fc receptors seem to prevent virus-specific IgG from activating antibody-dependent effector functions. We show that the mouse cytomegalovirus (MCMV) molecule fcr-1 promotes a rapid down-regulation of NKG2D ligands murine UL16-binding protein like transcript (MULT)-1 and H60 from the cell surface. Deletion of the m138/fcr-1 gene from the MCMV genome attenuates viral replication to natural killer (NK) cell response in an NKG2D-dependent manner in vivo. A distinct N-terminal module within the fcr-1 ectodomain in conjunction with the fcr-1 transmembrane domain was required to dispose MULT-1 to degradation in lysosomes. In contrast, down-modulation of H60 required the complete fcr-1 ectodomain, implying independent modes of fcr-1 interaction with the NKG2D ligands. The results establish a novel viral strategy for down-modulating NK cell responses and highlight the impressive diversity of Fc receptor functions.