Recognition of the class Ib molecule Qa-1(b) by putative activating receptors CD94/NKG2C and CD94/NKG2E on mouse natural killer cells

J Exp Med. 1999 Dec 20;190(12):1801-12. doi: 10.1084/jem.190.12.1801.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antigens, CD / physiology*
  • CHO Cells
  • Cloning, Molecular
  • Cricetinae
  • Histocompatibility Antigens Class I / physiology*
  • Humans
  • Killer Cells, Natural / physiology*
  • Lectins, C-Type*
  • Ligands
  • Membrane Glycoproteins / physiology*
  • Mice
  • Molecular Sequence Data
  • NK Cell Lectin-Like Receptor Subfamily C
  • NK Cell Lectin-Like Receptor Subfamily D
  • Receptors, Immunologic / physiology*
  • Receptors, Natural Killer Cell
  • Sequence Alignment


  • Antigens, CD
  • Histocompatibility Antigens Class I
  • KLRC1 protein, human
  • KLRC2 protein, human
  • KLRC3 protein, human
  • KLRD1 protein, human
  • Klrc1 protein, mouse
  • Klrc2 protein, mouse
  • Klrc3 protein, mouse
  • Klrd1 protein, mouse
  • Lectins, C-Type
  • Ligands
  • Membrane Glycoproteins
  • NK Cell Lectin-Like Receptor Subfamily C
  • NK Cell Lectin-Like Receptor Subfamily D
  • Receptors, Immunologic
  • Receptors, Natural Killer Cell

Associated data

  • GENBANK/AF195779