Cis association of Ly49A with MHC class I restricts natural killer cell inhibition

Nat Immunol. 2004 Mar;5(3):328-36. doi: 10.1038/ni1043. Epub 2004 Feb 15.


Natural killer (NK) cell function is negatively regulated by inhibitory receptors interacting with major histocompatibility complex class I molecules expressed on target cells. Here we show that the inhibitory Ly49A NK cell receptor not only binds to its H-2D(d) ligand expressed on potential target cells (in trans) but also is constitutively associated with H-2D(d) in cis (on the same cell). Cis association and trans interaction occur through the same binding site. Consequently, cis association restricts the number of Ly49A receptors available for binding of H-2D(d) on target cells and reduces NK cell inhibition through Ly49A. By lowering the threshold at which NK cell activation exceeds NK cell inhibition, cis interaction allows optimal discrimination of normal and abnormal host cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Ly / genetics
  • Antigens, Ly / metabolism
  • Antigens, Ly / physiology*
  • Binding Sites
  • Cell Line
  • Cell Line, Tumor
  • Cytotoxicity Tests, Immunologic
  • Cytotoxicity, Immunologic*
  • H-2 Antigens / metabolism
  • Histocompatibility Antigen H-2D
  • Histocompatibility Antigens Class I / metabolism*
  • Killer Cells, Natural / immunology*
  • Lectins, C-Type
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Immunological
  • Mosaicism
  • NK Cell Lectin-Like Receptor Subfamily A
  • Neoplasms / immunology
  • Receptors, Immunologic / metabolism
  • Receptors, Immunologic / physiology*
  • Receptors, NK Cell Lectin-Like
  • Transfection


  • Antigens, Ly
  • H-2 Antigens
  • Histocompatibility Antigen H-2D
  • Histocompatibility Antigens Class I
  • Klra1 protein, mouse
  • Lectins, C-Type
  • NK Cell Lectin-Like Receptor Subfamily A
  • Receptors, Immunologic
  • Receptors, NK Cell Lectin-Like