Impairment of NK cell function by NKG2D modulation in NOD mice

Immunity. 2003 Jan;18(1):41-51. doi: 10.1016/s1074-7613(02)00505-8.


Nonobese diabetic (NOD) mice, a model of insulin-dependent diabetes mellitus, have a defect in natural killer (NK) cell-mediated functions. Here we show impairment in an activating receptor, NKG2D, in NOD NK cells. While resting NK cells from C57BL/6 and NOD mice expressed equivalent levels of NKG2D, upon activation NOD NK cells but not C57BL/6 NK cells expressed NKG2D ligands, which resulted in downmodulation of the receptor. NKG2D-dependent cytotoxicity and cytokine production were decreased because of receptor modulation, accounting for the dysfunction. Modulation of NKG2D was mostly dependent on the YxxM motif of DAP10, the NKG2D-associated adaptor that activates phosphoinositide 3 kinase. These results suggest that NK cells may be desensitized by exposure to NKG2D ligands.

Publication types

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

MeSH terms

  • Animals
  • Coculture Techniques
  • Cytotoxicity, Immunologic
  • Diabetes Mellitus, Type 1 / immunology*
  • Enzyme Activation
  • Female
  • Interferon-gamma / biosynthesis
  • Killer Cells, Natural / immunology*
  • Ligands
  • Lymphocyte Activation
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • NK Cell Lectin-Like Receptor Subfamily K
  • Phosphatidylinositol 3-Kinases / metabolism
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Receptors, Natural Killer Cell
  • Transfection


  • Hcst protein, mouse
  • Klrk1 protein, mouse
  • Ligands
  • Membrane Proteins
  • NK Cell Lectin-Like Receptor Subfamily K
  • Raet1a protein, mouse
  • Receptors, Immunologic
  • Receptors, Natural Killer Cell
  • Interferon-gamma
  • Phosphatidylinositol 3-Kinases