Recognition of the class Ib molecule Qa-1(b) by putative activating receptors CD94/NKG2C and CD94/NKG2E on mouse natural killer cells.
The heterodimeric CD94/NKG2A receptor, expressed by mouse natural killer (NK) cells, transduces inhibitory signals upon recognition of its ligand, Qa-1(b), a nonclassical major histocompatibility complex class Ib molecule. Here we clone and express two additional receptors, CD94/NKG2C and CD94/NKG2E, which we show also bind to Qa-1(b). Within their extracellular carbohydrate recognition domains, NKG2C and NKG2E share extensive homology with NKG2A (93-95% amino acid similarity); however, NKG2C/E receptors differ from NKG2A in their cytoplasmic domains (only 33% similarity) and contain features that suggest that CD94/NKG2C and CD94/NKG2E may be activating receptors. We employ a novel blocking anti-NKG2 monoclonal antibody to provide the first direct evidence that CD94/NKG2 molecules are the only Qa-1(b) receptors on NK cells. Molecular analysis reveals that NKG2C and NKG2E messages are extensively alternatively spliced and approximately 20-fold less abundant than NKG2A message in NK cells. The organization of the mouse Cd94/Nkg2 gene cluster, presented here, shows striking similarity with that of the human, arguing that the entire CD94/NKG2 receptor system is relatively primitive in origin. Analysis of synonymous substitution frequencies suggests that within a species, NKG2 genes may maintain similarities with each other by concerted evolution, possibly involving gene conversion-like events. These findings have implications for understanding NK cells and also raise new possibilities for the role of Qa-1 in immune responses.
Vance
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Department of Molecular Biology, University of California, Berkeley, California 94720, USA.
Jamieson
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AM
Raulet
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DH
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D015395:Histocompatibility Antigens Class I / Q000502:physiology*; D006801:Humans; D007694:Killer Cells, Natural / Q000502:physiology*; D037181:Lectins, C-Type; D008024:Ligands; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D; D011971:Receptors, Immunologic / Q000502:physiology*; D055607:Receptors, Natural Killer Cell; D016415:Sequence Alignment
D015703:Antigens, CD; D015395:Histocompatibility Antigens Class I; C527054:KLRC1 protein, human; C527059:KLRC2 protein, human; C527062:KLRC3 protein, human; C497869:KLRD1 protein, human; C527057:Klrc1 protein, mouse; C527060:Klrc2 protein, mouse; C527063:Klrc3 protein, mouse; C497870:Klrd1 protein, mouse; D037181:Lectins, C-Type; D008024:Ligands; D008562:Membrane Glycoproteins; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell