Genetic variability of the major histocompatibility complex class I homologue encoded by human cytomegalovirus leads to differential binding to the inhibitory receptor ILT2.
Human cytomegalovirus carries a gene, UL18, that is homologous to cellular major histocompatibility complex (MHC) class I genes. Like MHC class I molecules, the protein product of the UL18 gene associates with beta2-microglobulin, and the stability of this complex depends on peptide loading. UL18 protein binds to ILT2 (CD85j), an inhibitory receptor present on B cells, monocytes, dendritic cells, T cells, and NK cells that also recognizes classical and nonclassical MHC molecules. These observations suggest that UL18 may play a role in viral immune evasion, but its real function is unclear. Since this molecule has similarity with polymorphic MHC proteins, we explored whether the UL18 gene varied between virus isolates. We report here that the UL18 gene varies significantly between virus isolates: amino acid substitutions were found in the predicted alpha1, alpha2, and alpha3 domains of the UL18 protein molecule. We also studied the ability of several variant UL18 proteins to bind to the ILT2 receptor. All of the variants tested bound to ILT2, but there were marked differences in the affinity of binding to this receptor. These differences were reflected in functional assays measuring inhibition of the cytotoxic capacity of NK cells via interaction with ILT2. In addition, the variants did not bind other members of the CD85 family. The implications of these data are discussed.
Valés-Gómez
Mar
M
Division of Immunology, Department of Pathology, Cambridge University, Tennis Court Rd., Cambridge CB2 1QP, UK.
Shiroishi
Mitsunori
M
Maenaka
Katsumi
K
Reyburn
Hugh T
HT
D015703:Antigens, CD / Q000378:metabolism*; D045744:Cell Line, Tumor; D003587:Cytomegalovirus / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000821:virology; D014644:Genetic Variation; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000502:physiology; D006801:Humans; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D008969:Molecular Sequence Data; D011971:Receptors, Immunologic / Q000378:metabolism*
D015703:Antigens, CD; D015395:Histocompatibility Antigens Class I; C105299:LILRB1 protein, human; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D011971:Receptors, Immunologic