Zoonotic orthopoxviruses encode a high-affinity antagonist of NKG2D.
NK and T lymphocytes express both activating and inhibiting receptors for various members of the major histocompatibility complex class I superfamily (MHCISF). To evade immunologic cytotoxicity, many viruses interfere with the function of these receptors, generally by altering the displayed profile of MHCISF proteins on host cells. Using a structurally constrained hidden Markov model, we discovered an orthopoxvirus protein, itself distantly class I-like, that acts as a competitive antagonist of the NKG2D activating receptor. This orthopoxvirus MHC class I-like protein (OMCP) is conserved among cowpox and monkeypox viruses, secreted by infected cells, and bound with high affinity by NKG2D of rodents and humans (K(D) approximately 30 and 0.2 nM, respectively). OMCP blocks recognition of host-encoded ligands and inhibits NKG2D-dependent killing by NK cells. This finding represents a novel mechanism for viral interference with NKG2D and sheds light on intercellular recognition events underlying innate immunity against emerging orthopoxviruses.
Campbell
Jessica A
JA
Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Trossman
David S
DS
Yokoyama
Wayne M
WM
Carayannopoulos
Leonidas N
LN
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D017124:Conserved Sequence / Q000235:genetics; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000378:metabolism*; D008390:Markov Chains; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D055655:NK Cell Lectin-Like Receptor Subfamily K; D018155:Orthopoxvirus / Q000235:genetics*; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055607:Receptors, Natural Killer Cell; D017422:Sequence Analysis, DNA
D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell