The coordinated activities of innate and adaptive immunity are critical for effective protection against viruses. To counter this, some viruses have evolved sophisticated strategies to circumvent immune cell recognition. In particular, cytomegaloviruses encode large arsenals of molecules that seek to subvert T cell and natural killer cell function via a remarkable array of mechanisms. Consequently, these ‘immunoevasins’ play a fundamental role in shaping the nature of the immune system by driving the evolution of new immune receptors and recognition mechanisms. Here, we review the diverse strategies adopted by cytomegaloviruses to target immune pathways and outline the host’s response.
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Murphy, E. & Shenk, T. Human cytomegalovirus genome. Curr. Top Microbiol. Immunol. 325, 1–19 (2008).
Rawlinson, W. D., Farrell, H. E. & Barrell, B. G. Analysis of the complete DNA sequence of murine cytomegalovirus. J. Virol. 70, 8833–8849 (1996).
Vink, C., Beuken, E. & Bruggeman, C. A. Complete DNA sequence of the rat cytomegalovirus genome. J. Virol. 74, 7656–7665 (2000).
Swinkels, B. W., Geelen, J. L., Wertheim-van Dillen, P., van Es, A. A. & van der Noordaa, J. Initial characterization of four cytomegalovirus strains isolated from chimpanzees. Brief report. Arch. Virol. 82, 125–128 (1984).
Powers, C. & Fruh, K. Rhesus CMV: an emerging animal model for human CMV. Med. Microbiol. Immunol. 197, 109–115 (2008).
Babic, M., Krmpotic, A. & Jonjic, S. All is fair in virus-host interactions: NK cells and cytomegalovirus. Trends Mol. Med. 17, 677–685 (2011).
Cannon, M. J., Schmid, D. S. & Hyde, T. B. Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev. Med. Virol. 20, 202–213 (2010).
Boppana, S. B. & Britt, W. J. in Cytomegaloviruses: from Molecular Pathogenesis to Intervention Vol. 2 (ed. Reddehase M. J.) (Caister Academic Press, 2013).
Manicklal, S., Emery, V. C., Lazzarotto, T., Boppana, S. B. & Gupta, R. K. The “silent” global burden of congenital cytomegalovirus. Clin. Microbiol. Rev. 26, 86–102 (2013).
Scalzo, A. A., Corbett, A. J., Rawlinson, W. D., Scott, G. M. & Degli-Esposti, M. A. The interplay between host and viral factors in shaping the outcome of cytomegalovirus infection. Immunol. Cell Biol. 85, 46–54 (2007).
Biron, C. A., Nguyen, K. B., Pien, G. C., Cousens, L. P. & Salazar-Mather, T. P. Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu. Rev. Immunol. 17, 189–220 (1999).
Orange, J. S. Natural killer cell deficiency. J. Allergy Clin. Immunol. 132, 515–525 (2013).
Stetson, D. B. et al. Constitutive cytokine mRNAs mark natural killer (NK) and NK T cells poised for rapid effector function. J. Exp. Med. 198, 1069–1076 (2003).
Fehniger, T. A. et al. Acquisition of murine NK cell cytotoxicity requires the translation of a pre-existing pool of granzyme B and perforin mRNAs. Immunity 26, 798–811 (2007).
Sun, J. C., Beilke, J. N. & Lanier, L. L. Adaptive immune features of natural killer cells. Nature 457, 557–561 (2009).
Cerwenka, A. & Lanier, L. L. Natural killer cell memory in infection, inflammation and cancer. Nat. Rev. Immunol. 16, 112–123 (2016).
Reddehase, M. J. Antigens and immunoevasins: opponents in cytomegalovirus immune surveillance. Nat. Rev. Immunol. 2, 831–844 (2002).
Jonjic, S., Mutter, W., Weiland, F., Reddehase, M. J. & Koszinowski, U. H. Site-restricted persistent cytomegalovirus infection after selective long-term depletion of CD4+ T lymphocytes. J. Exp. Med. 169, 1199–1212 (1989).
Jonjic, S., Pavic, I., Lucin, P., Rukavina, D. & Koszinowski, U. H. Efficacious control of cytomegalovirus infection after long-term depletion of CD8+ T lymphocytes. J. Virol. 64, 5457–5464 (1990).
Verma, S. et al. Cytomegalovirus-specific CD4 T cells are cytolytic and mediate vaccine protection. J. Virol. 90, 650–658 (2016).
Jeitziner, S. M., Walton, S. M., Torti, N. & Oxenius, A. Adoptive transfer of cytomegalovirus-specific effector CD4+ T cells provides antiviral protection from murine CMV infection. Eur. J. Immunol. 43 (2013).
Walton, S. M. et al. Absence of cross-presenting cells in the salivary gland and viral immune evasion confine cytomegalovirus immune control to effector CD4 T cells. PLOS Pathog. 7, e1002214 (2011).
Blyth, E. et al. Donor-derived CMV-specific T cells reduce the requirement for CMV-directed pharmacotherapy after allogeneic stem cell transplantation. Blood 121, 3745–3758 (2013).
Lilleri, D. et al. Human cytomegalovirus-specific CD4+ and CD8+ T-cell reconstitution in adult allogeneic hematopoietic stem cell transplant recipients and immune control of viral infection. Haematologica 93, 248–256 (2008).
Quinnan, G. V. et al. Cytotoxic t cells in cytomegalovirus infection: HLA-restricted T-lymphocyte and non-T-lymphocyte cytotoxic responses correlate with recovery from cytomegalovirus infection in bone-marrow-transplant recipients. N. Engl. J. Med. 307, 7–13 (1982).
Reusser, P., Riddell, S. R., Meyers, J. D. & Greenberg, P. D. Cytotoxic T-lymphocyte response to cytomegalovirus after human allogeneic bone marrow transplantation: pattern of recovery and correlation with cytomegalovirus infection and disease. Blood 78, 1373–1380 (1991).
Walter, E. A. et al. Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N. Engl. J. Med. 333, 1038–1044 (1995).
Gabanti, E. et al. Human cytomegalovirus (HCMV)-specific CD4+ and CD8+ T cells are both required for prevention of HCMV disease in seropositive solid-organ transplant recipients. PLOS ONE 9, e106044 (2014).
Gabanti, E. et al. Reconstitution of human cytomegalovirus-specific CD4+ T cells is critical for control of virus reactivation in hematopoietic stem cell transplant recipients but does not prevent organ infection. Biol. Blood Marrow Transplant. 21, 2192–2202 (2015).
Gamadia, L. E. et al. Primary immune responses to human CMV: a critical role for IFN-gamma-producing CD4+ T cells in protection against CMV disease. Blood 101, 2686–2692 (2003).
Andoniou, C. E. et al. Interaction between conventional dendritic cells and natural killer cells is integral to the activation of effective antiviral immunity. Nat. Immunol. 6, 1011–1019 (2005).
Andrews, D. M., Scalzo, A. A., Yokoyama, W. M., Smyth, M. J. & Degli-Esposti, M. A. Functional interactions between dendritic cells and NK cells during viral infection. Nat. Immunol. 4, 175–181 (2003).
Andrews, D. M. et al. Innate immunity defines the capacity of antiviral T cells to limit persistent infection. J. Exp. Med. 207, 1333–1343 (2010).
Dunn, W. et al. Functional profiling of a human cytomegalovirus genome. Proc. Natl Acad. Sci. USA 100, 14223–14228 (2003).
Davison, A. J. et al. Homology between the human cytomegalovirus RL11 gene family and human adenovirus E3 genes. J. Gen. Virol. 84, 657–663 (2003).
Fielding, C. A. et al. Control of immune ligands by members of a cytomegalovirus gene expansion suppresses natural killer cell activation. eLife 6, e22206 (2017). This study identifies the US12 family to be a major new hub of immune regulation.
Llano, M., Guma, M., Ortega, M., Angulo, A. & Lopez-Botet, M. Differential effects of US2, US6 and US11 human cytomegalovirus proteins on HLA class Ia and HLA-E expression: impact on target susceptibility to NK cell subsets. Eur. J. Immunol. 33, 2744–2754 (2003).
Jones, T. R. et al. Multiple independent loci within the human cytomegalovirus unique short region down-regulate expression of major histocompatibility complex class I heavy chains. J. Virol. 69, 4830–4841 (1995).
Gewurz, B. E. et al. Antigen presentation subverted: Structure of the human cytomegalovirus protein US2 bound to the class I molecule HLA-A2. Proc. Natl Acad. Sci. USA 98, 6794–6799 (2001).
Sekulin, K., Gorzer, I., Heiss-Czedik, D. & Puchhammer-Stockl, E. Analysis of the variability of CMV strains in the RL11D domain of the RL11 multigene family. Virus Genes 35, 577–583 (2007).
Fielding, C. A. et al. Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation. PLOS Pathog. 10, e1004058 (2014).
Pande, N. T., Powers, C., Ahn, K. & Fruh, K. Rhesus cytomegalovirus contains functional homologues of US2, US3, US6, and US11. J. Virol. 79, 5786–5798 (2005).
Powers, C. J. & Fruh, K. Signal peptide-dependent inhibition of MHC class I heavy chain translation by rhesus cytomegalovirus. PLOS Pathog. 4, e1000150 (2008).
Revilleza, M. J. et al. How the virus outsmarts the host: function and structure of cytomegalovirus MHC-I-like molecules in the evasion of natural killer cell surveillance. J. Biomed. Biotechnol. 2011, 724607 (2011).
Ziegler, H. et al. A mouse cytomegalovirus glycoprotein retains MHC class I complexes in the ERGIC/cis-Golgi compartments. Immunity 6, 57–66 (1997).
Hasan, M. et al. Selective down-regulation of the NKG2D ligand H60 by mouse cytomegalovirus m155 glycoprotein. J. Virol. 79, 2920–2930 (2005).
Krmpotic, A. et al. NK cell activation through the NKG2D ligand MULT-1 is selectively prevented by the glycoprotein encoded by mouse cytomegalovirus gene m145. J. Exp. Med. 201, 211–220 (2005).
Lodoen, M. B. et al. The cytomegalovirus m155 gene product subverts natural killer cell antiviral protection by disruption of H60-NKG2D interactions. J. Exp. Med. 200, 1075–1081 (2004).
Arase, H., Mocarski, E. S., Campbell, A. E., Hill, A. B. & Lanier, L. L. Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science 296, 1323–1326 (2002). This study (and also reference 164) reports the first direct interaction between a viral ligand and an activating NK cell receptor.
Berry, R. et al. The structure of the cytomegalovirus-encoded m04 glycoprotein, a prototypical member of the m02 family of immunoevasins. J. Biol. Chem. 289, 23753–23763 (2014).
Sgourakis, N. G. et al. The structure of mouse cytomegalovirus m04 protein obtained from sparse NMR data reveals a conserved fold of the m02-m06 viral immune modulator family. Structure 22, 1263–1273 (2014).
Aguilar, O. A. et al. A viral immunoevasin controls innate immunity by targeting the prototypical natural killer cell receptor family. Cell 169, 58–71 (2017). This study describes the identification of m12 as a ligand for inhibitory and activating NKR-P1 receptors (including NK1.1).
Babic, M. et al. Cytomegalovirus immunoevasin reveals the physiological role of “missing self” recognition in natural killer cell dependent virus control in vivo. J. Exp. Med. 207, 2663–2673 (2010).
Reusch, U. et al. A cytomegalovirus glycoprotein re-routes MHC class I complexes to lysosomes for degradation. EMBO J. 18, 1081–1091 (1999).
Goodwin, C. M., Ciesla, J. H. & Munger, J. Who’s driving? human cytomegalovirus, interferon, and NFkappaB signaling. Viruses 10, E447 (2018).
Rossjohn, J. et al. T cell antigen receptor recognition of antigen-presenting molecules. Annu. Rev. Immunol. 33, 169–200 (2015).
Ameres, S., Besold, K., Plachter, B. & Moosmann, A. CD8 T cell-evasive functions of human cytomegalovirus display pervasive MHC allele specificity, complementarity, and cooperativity. J. Immunol. 192, 5894–5905 (2014).
Barel, M. T. et al. Amino acid composition of alpha1/alpha2 domains and cytoplasmic tail of MHC class I molecules determine their susceptibility to human cytomegalovirus US11-mediated down-regulation. Eur. J. Immunol. 33 (2003).
Barel, M. T. et al. Human cytomegalovirus-encoded US2 differentially affects surface expression of MHC class I locus products and targets membrane-bound, but not soluble HLA-G1 for degradation. J. Immunol. 171, 6757–6765 (2003).
Wiertz, E. J. et al. The human cytomegalovirus US11 gene product dislocates MHC class I heavy chains from the endoplasmic reticulum to the cytosol. Cell 84, 769–779 (1996).
Wiertz, E. J. et al. Sec61-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction. Nature 384, 432–438 (1996). This study and reference 60 provide the first mechanistic insight into how HCMV downregulates MHC-I surface expression.
Furman, M. H., Ploegh, H. L. & Tortorella, D. Membrane-specific, host-derived factors are required for US2- and US11-mediated degradation of major histocompatibility complex class I molecules. J. Biol. Chem. 277, 3258–3267 (2002).
Lee, S. O. et al. Functional dissection of HCMV US11 in mediating the degradation of MHC class I molecules. Biochem. Biophys. Res. Commun. 330, 1262–1267 (2005).
Lilley, B. N. & Ploegh, H. L. A membrane protein required for dislocation of misfolded proteins from the ER. Nature 429, 834–840 (2004).
Hsu, J. L. et al. Plasma membrane profiling defines an expanded class of cell surface proteins selectively targeted for degradation by HCMV US2 in cooperation with UL141. PLOS Pathog. 11, e1004811 (2015). This study uses proteomics to reveal the full breadth of molecules that can be targeted by US2 and highlights how a single immunoevasin can modulate multiple immune-related pathways.
Vahdati-Ben Arieh, S. et al. A single viral protein HCMV US2 affects antigen presentation and intracellular iron homeostasis by degradation of classical HLA class I and HFE molecules. Blood 101, 2858–2864 (2003).
Ben-Arieh, S. V. et al. Human cytomegalovirus protein US2 interferes with the expression of human HFE, a nonclassical class I major histocompatibility complex molecule that regulates iron homeostasis. J. Virol. 75, 10557–10562 (2001).
Han, J. et al. Human cytomegalovirus (HCMV) US2 protein interacts with human CD1d (hCD1d) and down-regulates invariant NKT (iNKT) cell activity. Mol. Cells 36, 455–464 (2013).
Tomazin, R. et al. Cytomegalovirus US2 destroys two components of the MHC class II pathway, preventing recognition by CD4+ T cells. Nat. Med. 5, 1039–1043 (1999).
Park, B., Spooner, E., Houser, B. L., Strominger, J. L. & Ploegh, H. L. The HCMV membrane glycoprotein US10 selectively targets HLA-G for degradation. J. Exp. Med. 207, 2033–2041 (2010).
Furman, M. H., Dey, N., Tortorella, D. & Ploegh, H. L. The human cytomegalovirus US10 gene product delays trafficking of major histocompatibility complex class I molecules. J. Virol. 76, 11753–11756 (2002).
Blees, A. et al. Structure of the human MHC-I peptide-loading complex. Nature 551, 525–528 (2017).
Park, B. et al. Human cytomegalovirus inhibits tapasin-dependent peptide loading and optimization of the MHC class I peptide cargo for immune evasion. Immunity 20, 71–85 (2004).
Jones, T. R. et al. Human cytomegalovirus US3 impairs transport and maturation of major histocompatibility complex class I heavy chains. Proc. Natl Acad. Sci. USA 93, 11327–11333 (1996).
Huard, B. & Fruh, K. A role for MHC class I down-regulation in NK cell lysis of herpes virus-infected cells. Eur. J. Immunol. 30, 509–515 (2000).
Ahn, K. et al. The ER-luminal domain of the HCMV glycoprotein US6 inhibits peptide translocation by TAP. Immunity 6, 613–621 (1997).
Lehner, P. J., Karttunen, J. T., Wilkinson, G. W. & Cresswell, P. The human cytomegalovirus US6 glycoprotein inhibits transporter associated with antigen processing-dependent peptide translocation. Proc. Natl Acad. Sci. USA 94, 6904–6909 (1997).
Hewitt, E. W., Gupta, S. S. & Lehner, P. J. The human cytomegalovirus gene product US6 inhibits ATP binding by TAP. EMBO J. 20, 387–396 (2001).
Ziegler, H., Muranyi, W., Burgert, H. G., Kremmer, E. & Koszinowski, U. H. The luminal part of the murine cytomegalovirus glycoprotein gp40 catalyzes the retention of MHC class I molecules. EMBO J. 19, 870–881 (2000).
Ramnarayan, V. R. et al. Cytomegalovirus gp40/m152 uses TMED10 as ER anchor to retain MHC class I. Cell Rep. 23, 3068–3077 (2018).
Karre, K., Ljunggren, H. G., Piontek, G. & Kiessling, R. Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature 319 (1986).
Beck, S. & Barrell, B. G. Human cytomegalovirus encodes a glycoprotein homologous to MHC class-I antigens. Nature 331, 269–272 (1988).
Browne, H., Smith, G., Beck, S. & Minson, T. A complex between the MHC class I homologue encoded by human cytomegalovirus and beta 2 microglobulin. Nature 347, 770–772 (1990).
Fahnestock, M. L. et al. The MHC class I homolog encoded by human cytomegalovirus binds endogenous peptides. Immunity 3, 583–590 (1995). This study and references 82 and 83 describe the first identification of an HCMV-encoded MHC-I homologue that was subsequently shown to inhibit NK cell activation (Reyburn et al., 1997).
Chapman, T. L., Heikeman, A. P. & Bjorkman, P. J. The inhibitory receptor LIR-1 uses a common binding interaction to recognize class I MHC molecules and the viral homolog UL18. Immunity 11, 603–613 (1999).
Prod’homme, V. et al. The human cytomegalovirus MHC class I homolog UL18 inhibits LIR-1+but activates LIR-1- NK cells. J. Immunol. 178, 4473–4481 (2007).
Reyburn, H. T. et al. The class I MHC homologue of human cytomegalovirus inhibits attack by natural killer cells. Nature 386, 514–517 (1997). This is the first description of an HCMV-encoded immunoevasin that subverts NK cell function.
Leong, C. C. et al. Modulation of natural killer cell cytotoxicity in human cytomegalovirus infection: the role of endogenous class I major histocompatibility complex and a viral class I homolog. J. Exp. Med. 187, 1681–1687 (1998).
Yang, Z. & Bjorkman, P. J. Structure of UL18, a peptide-binding viral MHC mimic, bound to a host inhibitory receptor. Proc. Natl Acad. Sci. USA 105, 10095–10100 (2008).
Kim, Y. et al. Human cytomegalovirus UL18 utilizes US6 for evading the NK and T-cell responses. PLoS Pathog. 4, e1000123 (2008).
Park, B. et al. The MHC class I homolog of human cytomegalovirus is resistant to down-regulation mediated by the unique short region protein (US)2, US3, US6, and US11 gene products. J. Immunol. 168, 3464–3469 (2002).
Adams, E. J. et al. Structural elucidation of the m157 mouse cytomegalovirus ligand for Ly49 natural killer cell receptors. Proc. Natl Acad. Sci. USA 104, 10128–10133 (2007).
Aguilar, O. A. et al. Modulation of Clr ligand expression and NKR-P1 receptor function during murine cytomegalovirus infection. J. Innate Immun. 7, 584–600 (2015).
Kirkham, C. L. et al. Interferon-dependent induction of Clr-b during mouse cytomegalovirus infection protects bystander cells from natural killer cells via nkr-p1b-mediated inhibition. J. Innate Immun. 9, 343–358 (2017).
Voigt, S. et al. Cytomegalovirus evasion of innate immunity by subversion of the NKR-P1B:Clr-b missing-self axis. Immunity 26, 617–627 (2007).
Voigt, S., Sandford, G. R., Ding, L. & Burns, W. H. Identification and characterization of a spliced C-type lectin-like gene encoded by rat cytomegalovirus. J. Virol. 75, 603–611 (2001).
Braud, V. M. et al. HLA-E binds to natural killer cell receptors CD94/NKG2A, B and C. Nature 391, 795–799 (1998).
Braud, V., Jones, E. Y. & McMichael, A. The human major histocompatibility complex class Ib molecule HLA-E binds signal sequence-derived peptides with primary anchor residues at positions 2 and 9. Eur. J. Immunol. 27, 1164–1169 (1997).
Tomasec, P. et al. Surface expression of HLA-E, an inhibitor of natural killer cells, enhanced by human cytomegalovirus gpUL40. Science 287, 1031 (2000). This study finds that the leader sequence of gpUL40 binds HLA-E and upregulates its surface expression, thereby protecting infected cells from NK cell attack.
Ulbrecht, M. et al. Cutting edge: the human cytomegalovirus UL40 gene product contains a ligand for HLA-E and prevents NK cell-mediated lysis. J. Immunol. 164, 5019–5022 (2000).
Cerboni, C. et al. Synergistic effect of IFN-gamma and human cytomegalovirus protein UL40 in the HLA-E-dependent protection from NK cell-mediated cytotoxicity. Eur. J. Immunol. 31, 2926–2935 (2001).
Heatley, S. L. et al. Polymorphism in human cytomegalovirus UL40 impacts on recognition of human leukocyte antigen-E (HLA-E) by natural killer cells. J. Biol. Chem. 288, 8679–8690 (2013).
Wang, E. C. et al. UL40-mediated NK evasion during productive infection with human cytomegalovirus. Proc. Natl Acad. Sci. USA 99, 7570–7575 (2002).
Hoare, H. L. et al. Structural basis for a major histocompatibility complex class Ib-restricted T cell response. Nat. Immunol. 7, 256–264 (2006).
Sullivan, L. C. et al. A conserved energetic footprint underpins recognition of human leukocyte antigen-E by two distinct alphabeta T cell receptors. J. Biol. Chem. 292, 21149–21158 (2017).
Kleijnen, M. F. et al. A mouse cytomegalovirus glycoprotein, gp34, forms a complex with folded class I MHC molecules in the ER which is not retained but is transported to the cell surface. EMBO J. 16, 685–694 (1997).
Corbett, A. J., Forbes, C. A., Moro, D. & Scalzo, A. A. Extensive sequence variation exists among isolates of murine cytomegalovirus within members of the m02 family of genes. J. Gen. Virol. 88, 758–769 (2007).
Zeleznjak, J. et al. The complex of MCMV proteins and MHC class I evades NK cell control and drives the evolution of virus-specific activating Ly49 receptors. J. Exp. Med. 216, 1809–1827 (2019).
Orr, M. T., Murphy, W. J. & Lanier, L. L. ‘Unlicensed’ natural killer cells dominate the response to cytomegalovirus infection. Nat. Immunol. 11, 321–327 (2010).
Slavuljica, I., Krmpotic, A. & Jonjic, S. Manipulation of NKG2D ligands by cytomegaloviruses: impact on innate and adaptive immune response. Front. Immunol. 2, 85 (2011).
Jonjic, S., Babic, M., Polic, B. & Krmpotic, A. Immune evasion of natural killer cells by viruses. Curr. Opin. Immunol. 20, 30–38 (2008).
Lanier, L. L. NKG2D Receptor and its ligands in host defense. Cancer Immunol. Res. 3, 575–582 (2015).
Ashiru, O. et al. NKG2D ligand MICA is retained in the cis-Golgi apparatus by human cytomegalovirus protein UL142. J. Virol. 83, 12345–12354 (2009).
Chalupny, N. J., Rein-Weston, A., Dosch, S. & Cosman, D. Down-regulation of the NKG2D ligand MICA by the human cytomegalovirus glycoprotein UL142. Biochem. Biophys. Res. Commun. 346, 175–181 (2006).
Dassa, L. et al. The human cytomegalovirus protein UL148a downregulates the nk cell-activating ligand mica to avoid NK cell attack. J. Virol. 92 (2018).
Seidel, E. et al. Dynamic co-evolution of host and pathogen: HCMV downregulates the prevalent allele MICA *008 to escape elimination by NK cells. Cell Rep. 10, 968–982 (2015).
Dunn, C. et al. Human cytomegalovirus glycoprotein UL16 causes intracellular sequestration of NKG2D ligands, protecting against natural killer cell cytotoxicity. J. Exp. Med. 197, 1427–1439 (2003). Collectively, this study and references 120 and 123 highlight that both HCMV and MCMV have evolved molecules that interfere with surface expression of NKG2D ligands.
Stern-Ginossar, N. et al. Host immune system gene targeting by a viral miRNA. Science 317, 376–381 (2007).
Raulet, D. H., Gasser, S., Gowen, B. G., Deng, W. & Jung, H. Regulation of ligands for the NKG2D activating receptor. Annu. Rev. Immunol. 31, 413–441 (2013).
Lodoen, M. et al. NKG2D-mediated natural killer cell protection against cytomegalovirus is impaired by viral gp40 modulation of retinoic acid early inducible 1 gene molecules. J. Exp. Med. 197, 1245–1253 (2003).
Arapovic, J. et al. Differential susceptibility of RAE-1 isoforms to mouse cytomegalovirus. J. Virol. 83, 8198–8207 (2009).
Zhi, L. et al. Direct interaction of the mouse cytomegalovirus m152/gp40 immunoevasin with RAE-1 isoforms. Biochemistry 49, 2443–2453 (2010).
Lenac, T. et al. The herpesviral Fc receptor fcr-1 down-regulates the NKG2D ligands MULT-1 and H60. J. Exp. Med. 203, 1843–1850 (2006).
Shibuya, A. et al. DNAM-1, a novel adhesion molecule involved in the cytolytic function of T lymphocytes. Immunity 4, 573–581 (1996).
Bottino, C. et al. Identification of PVR (CD155) and nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule. J. Exp. Med. 198, 557–567 (2003).
Tahara-Hanaoka, S. et al. Functional characterization of DNAM-1 (CD226) interaction with its ligands PVR (CD155) and nectin-2 (PRR-2/CD112). Int. Immunol. 16, 533–538 (2004).
Lenac Rovis, T. et al. Inflammatory monocytes and NK cells play a crucial role in DNAM-1-dependent control of cytomegalovirus infection. J. Exp. Med. 213, 1835–1850 (2016).
Pignoloni, B. et al. Distinct roles for human cytomegalovirus immediate early proteins IE1 and IE2 in the transcriptional regulation of MICA and PVR/CD155 expression. J. Immunol. 197, 4066–4078 (2016).
Prod’homme, V. et al. Human cytomegalovirus UL141 promotes efficient downregulation of the natural killer cell activating ligand CD112. J. Gen. Virol. 91, 2034–2039 (2010).
Tomasec, P. et al. Downregulation of natural killer cell-activating ligand CD155 by human cytomegalovirus UL141. Nat. Immunol. 6, 181–188 (2005).
Nemcovicova, I., Benedict, C. A. & Zajonc, D. M. Structure of human cytomegalovirus UL141 binding to TRAIL-R2 reveals novel, non-canonical death receptor interactions. PLOS Pathog. 9, e1003224 (2013).
Smith, W. et al. Human cytomegalovirus glycoprotein UL141 targets the TRAIL death receptors to thwart host innate antiviral defenses. Cell Host Microbe 13, 324–335 (2013).
Chan, C. J. et al. The receptors CD96 and CD226 oppose each other in the regulation of natural killer cell functions. Nat. Immunol. 15, 431–438 (2014).
Deuss, F. A., Gully, B. S., Rossjohn, J. & Berry, R. Recognition of nectin-2 by the natural killer cell receptor T cell immunoglobulin and ITIM domain (TIGIT). J. Biol. Chem. 292, 11413–11422 (2017).
Deuss, F. A., Watson, G. M., Fu, Z., Rossjohn, J. & Berry, R. Structural basis for CD96 immune receptor recognition of nectin-like protein-5, CD155. Structure 27, 219–228 e213 (2019).
Stengel, K. F. et al. Structure of TIGIT immunoreceptor bound to poliovirus receptor reveals a cell-cell adhesion and signaling mechanism that requires cis-trans receptor clustering. Proc. Natl Acad. Sci. USA 109, 5399–5404 (2012).
Deuss, F. A. et al. Structural basis for the recognition of nectin-like protein-5 by the human activating immune receptor, DNAM-1. J. Biol. Chem. 294, 12534–12546 (2019).
Valiante, N. M. & Trinchieri, G. Identification of a novel signal transduction surface molecule on human cytotoxic lymphocytes. J. Exp. Med. 178, 1397–1406 (1993).
Garni-Wagner, B. A., Purohit, A., Mathew, P. A., Bennett, M. & Kumar, V. A novel function-associated molecule related to non-MHC-restricted cytotoxicity mediated by activated natural killer cells and T cells. J. Immunol. 151, 60–70 (1993).
Lee, K. M. et al. 2B4 acts as a non-major histocompatibility complex binding inhibitory receptor on mouse natural killer cells. J. Exp. Med. 199, 1245–1254 (2004).
Zarama, A. et al. Cytomegalovirus m154 hinders CD48 cell-surface expression and promotes viral escape from host natural killer cell control. PLOS Pathog. 10, e1004000 (2014).
Romo, N. et al. Natural killer cell-mediated response to human cytomegalovirus-infected macrophages is modulated by their functional polarization. J. Leukoc. Biol. 90, 717–726 (2011).
Martinez-Vicente, P. et al. Subversion of natural killer cell responses by a cytomegalovirus-encoded soluble CD48 decoy receptor. PLOS Pathog. 15, e1007658 (2019).
Kruse, P. H., Matta, J., Ugolini, S. & Vivier, E. Natural cytotoxicity receptors and their ligands. Immunol. Cell Biol. 92, 221–229 (2014).
Arnon, T. I. et al. Inhibition of the NKp30 activating receptor by pp65 of human cytomegalovirus. Nat. Immunol. 6, 515–523 (2005).
Charpak-Amikam, Y. et al. Human cytomegalovirus escapes immune recognition by NK cells through the downregulation of B7-H6 by the viral genes US18 and US20. Sci. Rep. 7, 8661 (2017).
Miletic, A., Krmpotic, A. & Jonjic, S. The evolutionary arms race between NK cells and viruses: who gets the short end of the stick? Eur. J. Immunol. 43, 867–877 (2013).
Hogarth, P. M. & Pietersz, G. A. Fc receptor-targeted therapies for the treatment of inflammation, cancer and beyond. Nat. Rev. Drug Discov. 11, 311–331 (2012).
Ross, S. A. et al. Cytomegalovirus reinfections in healthy seroimmune women. J. Infect. Dis. 201, 386–389 (2010).
Furukawa, T., Hornberger, E., Sakuma, S. & Plotkin, S. A. Demonstration of immunoglobulin G receptors induced by human cytomegalovirus. J. Clin. Microbiol. 2, 332–336 (1975).
Atalay, R. et al. Identification and expression of human cytomegalovirus transcription units coding for two distinct Fcgamma receptor homologs. J. Virol. 76, 8596–8608 (2002).
Cortese, M. et al. Recombinant human cytomegalovirus (HCMV) RL13 binds human immunoglobulin G Fc. PLOS ONE 7, e50166 (2012).
Lilley, B. N., Ploegh, H. L. & Tirabassi, R. S. Human cytomegalovirus open reading frame TRL11/IRL11 encodes an immunoglobulin G Fc-binding protein. J. Virol. 75, 11218–11221 (2001).
Corrales-Aguilar, E., Hoffmann, K. & Hengel, H. CMV-encoded Fcgamma receptors: modulators at the interface of innate and adaptive immunity. Semin. Immunopathol. 36, 627–640 (2014).
Sprague, E. R. et al. The human cytomegalovirus Fc receptor gp68 binds the Fc CH2-CH3 interface of immunoglobulin G. J. Virol. 82, 3490–3499 (2008).
Ndjamen, B., Joshi, D. S., Fraser, S. E. & Bjorkman, P. J. Characterization of antibody bipolar bridging mediated by the human cytomegalovirus Fc receptor gp68. J. Virol. 90, 3262–3267 (2016).
Thale, R., Lucin, P., Schneider, K., Eggers, M. & Koszinowski, U. H. Identification and expression of a murine cytomegalovirus early gene coding for an Fc receptor. J. Virol. 68, 7757–7765 (1994).
Crnkovic-Mertens, I. et al. Virus attenuation after deletion of the cytomegalovirus Fc receptor gene is not due to antibody control. J. Virol. 72, 1377–1382 (1998).
Kolb, P. et al. Identification and functional characterization of a novel fc gamma-binding glycoprotein in rhesus cytomegalovirus. J. Virol. 93, e02077–18 (2019).
Abi-Rached, L. & Parham, P. Natural selection drives recurrent formation of activating killer cell immunoglobulin-like receptor and Ly49 from inhibitory homologues. J. Exp. Med. 201, 1319–1332 (2005). This study investigates the evolutionary history of KIRs and Ly49 receptors and proposes a model in which the activating receptors evolved more recently from their inhibitory counterparts in response to selective pressure induced by pathogens.
Corbett, A. J., Coudert, J. D., Forbes, C. A. & Scalzo, A. A. Functional consequences of natural sequence variation of murine cytomegalovirus m157 for Ly49 receptor specificity and NK cell activation. J. Immunol. 186, 1713–1722 (2011).
Berry, R. et al. Targeting of a natural killer cell receptor family by a viral immunoevasin. Nat. Immunol. 14, 699–705 (2013). This study reports the structure of the Ly49H–m157 complex and demonstrates that this immunoevasin targets the membrane proximal stalk region of the receptor.
Dorner, B. G. et al. Coordinate expression of cytokines and chemokines by NK cells during murine cytomegalovirus infection. J. Immunol. 172, 3119–3131 (2004).
Smith, H. R. et al. Recognition of a virus-encoded ligand by a natural killer cell activation receptor. Proc. Natl Acad. Sci. USA 99, 8826–8831 (2002).
Desrosiers, M. P. et al. 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. Nat. Genet. 37, 593–599 (2005).
Pyzik, M. et al. Distinct MHC class I-dependent NK cell-activating receptors control cytomegalovirus infection in different mouse strains. J. Exp. Med. 208, 1105–1117 (2011).
Kielczewska, A. et al. Ly49P recognition of cytomegalovirus-infected cells expressing H2-Dk and CMV-encoded m04 correlates with the NK cell antiviral response. J. Exp. Med. 206, 515–523 (2009). This study and references 165 and 166 show that activating Ly49 receptors can recognize infected cells via a novel mechanism that is dependent on certain MHC-I allotypes.
Guma, M. et al. Expansion of CD94/NKG2C+ NK cells in response to human cytomegalovirus-infected fibroblasts. Blood 107, 3624–3631 (2006).
Hammer, Q. et al. Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells. Nat. Immunol. 19, 453–463 (2018).
Rolle, A. et al. IL-12-producing monocytes and HLA-E control HCMV-driven NKG2C+ NK cell expansion. J. Clin. Invest. 124, 5305–5316 (2014).
Voigt, V. et al. Murine cytomegalovirus m157 mutation and variation leads to immune evasion of natural killer cells. Proc. Natl Acad. Sci. USA 100, 13483–13488 (2003).
French, A. R. et al. Escape of mutant double-stranded DNA virus from innate immune control. Immunity 20, 747–756 (2004).
McWhorter, A. R. et al. Natural killer cell dependent within-host competition arises during multiple MCMV infection: consequences for viral transmission and evolution. PLOS Pathog. 9, e1003111 (2013).
Vivian, J. P. et al. Killer cell immunoglobulin-like receptor 3DL1-mediated recognition of human leukocyte antigen B. Nature 479, 401–405 (2011).
Saunders, P. M. et al. A bird’s eye view of NK cell receptor interactions with their MHC class I ligands. Immunol. Rev. 267, 148–166 (2015).
Cook, M. et al. Donor KIR genotype has a major influence on the rate of cytomegalovirus reactivation following T-cell replete stem cell transplantation. Blood 107, 1230–1232 (2006).
van Duin, D. et al. KIR and HLA interactions are associated with control of primary CMV infection in solid organ transplant recipients. Am. J. Transpl. 14, 156–162 (2014).
Khakoo, S. I. et al. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science 305, 872–874 (2004).
Martin, M. P. et al. Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1. Nat. Genet. 39, 733–740 (2007).
Ashiru, O. et al. A GPI anchor explains the unique biological features of the common NKG2D-ligand allele MICA*008. Biochem. J. 454, 295–302 (2013).
Mizuki, N. et al. Triplet repeat polymorphism in the transmembrane region of the MICA gene: a strong association of six GCT repetitions with Behcet disease. Proc. Natl Acad. Sci. USA 94, 1298–1303 (1997).
Romphruk, A. V. et al. Diversity of MICA (PERB11.1) and HLA haplotypes in northeastern Thais. Tissue Antigens 58, 83–89 (2001).
Tian, W., Boggs, D. A., Ding, W. Z., Chen, D. F. & Fraser, P. A. MICA genetic polymorphism and linkage disequilibrium with HLA-B in 29 African-American families. Immunogenetics 53, 724–728 (2001).
Zhang, Y. et al. MICA polymorphism in South American Indians. Immunogenetics 53, 900–906 (2002).
van de Weijer, M. L., Luteijn, R. D. & Wiertz, E. J. Viral immune evasion: Lessons in MHC class I antigen presentation. Semin. Immunol. 27, 125–137 (2015).
De Pelsmaeker, S., Romero, N., Vitale, M. & Favoreel, H. W. Herpesvirus evasion of natural killer cells. J. Virol. 92, e02105–e02117 (2018).
Matschulla, T. et al. A highly conserved sequence of the viral TAP inhibitor ICP47 is required for freezing of the peptide transport cycle. Sci. Rep. 7, 2933 (2017).
Oldham, M. L., Grigorieff, N. & Chen, J. Structure of the transporter associated with antigen processing trapped by herpes simplex virus. eLife 5, e21829 (2016).
Bennett, E. M., Bennink, J. R., Yewdell, J. W. & Brodsky, F. M. Cutting edge: adenovirus E19 has two mechanisms for affecting class I MHC expression. J. Immunol. 162, 5049–5052 (1999).
Barkal, A. A. et al. Engagement of MHC class I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy. Nat. Immunol. 19, 76–84 (2018).
Dougall, W. C., Kurtulus, S., Smyth, M. J. & Anderson, A. C. TIGIT and CD96: new checkpoint receptor targets for cancer immunotherapy. Immunol. Rev. 276, 112–120 (2017).
Tanaka, M. et al. The Inhibitory NKR-P1B:Clr-b recognition axis facilitates detection of oncogenic transformation and cancer immunosurveillance. Cancer Res. 78, 3589–3603 (2018).
Cox, J. H., Yewdell, J. W., Eisenlohr, L. C., Johnson, P. R. & Bennink, J. R. Antigen presentation requires transport of MHC class I molecules from the endoplasmic reticulum. Science 247, 715–718 (1990).
Weizman, O. E. et al. Mouse cytomegalovirus-experienced ILC1s acquire a memory response dependent on the viral glycoprotein m12. Nat. Immunol. 20, 1004–1011 (2019).
Lucas, A. & McFadden, G. Secreted immunomodulatory viral proteins as novel biotherapeutics. J. Immunol. 173, 4765–4774 (2004).
Altomonte, J. et al. Enhanced oncolytic potency of vesicular stomatitis virus through vector-mediated inhibition of NK and NKT cells. Cancer Gene Ther. 16, 266–278 (2009).
Kim, J. S. et al. Human cytomegalovirus UL18 alleviated human NK-mediated swine endothelial cell lysis. Biochem. Biophys. Res. Commun. 315, 144–150 (2004).
Wilkinson, G. W. et al. Human cytomegalovirus: taking the strain. Med. Microbiol. Immunol. 204, 273–284 (2015).
Cha, T. A. et al. Human cytomegalovirus clinical isolates carry at least 19 genes not found in laboratory strains. J. Virol. 70, 78–83 (1996).
Cerboni, C. et al. Human cytomegalovirus strain-dependent changes in NK cell recognition of infected fibroblasts. J. Immunol. 164, 4775–4782 (2000).
Stanton, R. J. et al. Reconstruction of the complete human cytomegalovirus genome in a BAC reveals RL13 to be a potent inhibitor of replication. J. Clin. Invest. 120, 3191–3208 (2010).
Murrell, I. et al. Genetic stability of bacterial artificial chromosome-derived human cytomegalovirus during culture in vitro. J. Virol. 90, 3929–3943 (2016).
Coaquette, A. et al. Mixed cytomegalovirus glycoprotein B genotypes in immunocompromised patients. Clin. Infect. Dis. 39, 155–161 (2004).
Cudini, J. et al. Human cytomegalovirus haplotype reconstruction reveals high diversity due to superinfection and evidence of within-host recombination. Proc. Natl Acad. Sci. USA 116, 5693–5698 (2019).
Smith, C. et al. Coinfection with human cytomegalovirus genetic variants in transplant recipients and its impact on antiviral t cell immune reconstitution. J. Virol. 90, 7497–7507 (2016).
Suarez, N. M. et al. Human cytomegalovirus genomes sequenced directly from clinical material: variation, multiple-strain infection, recombination and gene loss. J. Infect. Dis. 220, 781–791 (2019).
Smith, L. M., McWhorter, A. R., Masters, L. L., Shellam, G. R. & Redwood, A. J. Laboratory strains of murine cytomegalovirus are genetically similar to but phenotypically distinct from wild strains of virus. J. Virol. 82, 6689–6696 (2008).
Martins, J. P. et al. Strain-specific antibody therapy prevents cytomegalovirus reactivation after transplantation. Science 363, 288–293 (2019).
Reddehase, M. J. & Lemmermann, N. A. W. Mouse model of cytomegalovirus disease and immunotherapy in the immunocompromised host: predictions for medical translation that survived the “test of time”. Viruses 10, E693 (2018).
Petrie, E. J. et al. CD94-NKG2A recognition of human leukocyte antigen (HLA)-E bound to an HLA class I leader sequence. J. Exp. Med. 205, 725–735 (2008).
Li, P., McDermott, G. & Strong, R. K. Crystal structures of RAE-1beta and its complex with the activating immunoreceptor NKG2D. Immunity 16, 77–86 (2002).
Li, P. et al. Complex structure of the activating immunoreceptor NKG2D and its MHC class I-like ligand MICA. Nat. Immunol. 2, 443–451 (2001).
Radaev, S., Rostro, B., Brooks, A. G., Colonna, M. & Sun, P. D. Conformational plasticity revealed by the cocrystal structure of NKG2D and its class I MHC-like ligand ULBP3. Immunity 15, 1039–1049 (2001).
Zuo, J. et al. A disease-linked ULBP6 polymorphism inhibits NKG2D-mediated target cell killing by enhancing the stability of NKG2D ligand binding. Sci. Signal 10, eaai8904 (2017).
Wang, R. et al. Structural basis of mouse cytomegalovirus m152/gp40 interaction with RAE1gamma reveals a paradigm for MHC/MHC interaction in immune evasion. Proc. Natl Acad. Sci. USA 109, E3578–E3587 (2012).
Muller, S., Zocher, G., Steinle, A. & Stehle, T. Structure of the HCMV UL16-MICB complex elucidates select binding of a viral immunoevasin to diverse NKG2D ligands. PLOS Pathog. 6, e1000723 (2010).
Balaji, G. R. et al. Recognition of host Clr-b by the inhibitory NKR-P1B receptor provides a basis for missing-self recognition. Nat. Commun. 9, 4623 (2018).
Gao, G. F. et al. Crystal structure of the complex between human CD8alpha(alpha) and HLA-A2. Nature 387, 630–634 (1997).
The authors acknowledge funding from the National Health and Medical Research Council of Australia to R.B. (APP1109901) and M.A.D-E. (GNT1119298), the Deutsche Forschungsgemeinschaft-funded research unit Advanced Concepts in Cellular Immune Control of Cytomegalovirus (FOR 2830) project ‘Solving the m04 paradox: evasion of missing-self recognition and CD8 T cell killing by MAT uORF’ to S.J. (JO 1634/1-1), the grant KK.01.1.1.01.0006, awarded to the Scientific Centre of Excellence for Virus Immunology and Vaccines and co-financed by the European Regional Development Fund, to S.J. and the Australian Research Council to J.R. (FL160100049).
Nature Reviews Immunology thanks A. Cerwenka and C. Biron for their contribution to the peer review of this work.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Paired receptors
Closely related receptors that bind to the same or similar ligands but trigger opposing functional effects (for example, stimulatory versus inhibitory).
- V-type immunoglobulin domain
A compact protein module comprising two β-sheets arranged into a β-sandwich fold. 'V' refers to ‘variable’ indicating a subclass of immunoglobulin domains that possess nine β-strands and resemble those located within the variable portion of antibodies.
- ‘Missing-self’ recognition
A term used to describe how the downregulation of self-molecules, which act as ligands for inhibitory receptors, can trigger natural killer cell activation.
- Sec61 complex
A dynamic multiprotein channel that, in eukaryotic cells, is located within the endoplasmic reticulum membrane. It mediates the membrane insertion and translocation of most proteins that reside in the endomembrane system or are destined for secretion.
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Berry, R., Watson, G.M., Jonjic, S. et al. Modulation of innate and adaptive immunity by cytomegaloviruses. Nat Rev Immunol 20, 113–127 (2020). https://doi.org/10.1038/s41577-019-0225-5
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