Sustained localized expression of ligand for the activating NKG2D receptor impairs natural cytotoxicity in vivo and reduces tumor immunosurveillance

Nat Immunol. 2005 Sep;6(9):928-37. doi: 10.1038/ni1239. Epub 2005 Aug 14.


Upregulation of the inducible gene products MICA (human) and Rae-1 (mouse) may promote tumor surveillance and autoimmunity by engaging the activating receptor NKG2D on natural killer (NK) cells and T cells. Nevertheless, sustained expression of MICA by tumors can also elicit NKG2D downregulation, perhaps indicating 'immunoevasion'. Investigating this paradox, we report here that constitutive Rae-1epsilon transgene expression in normal epithelium elicited local and systemic NKG2D downregulation, generalized but reversible defects in NK cell-mediated cytotoxicity and mild CD8(+) T cell defects. The extent of NKG2D downregulation correlated well with the incidence and progression of cutaneous carcinogenesis, emphasizing the utility of NKG2D as a marker of tumor resistance. Thus, NKG2D engagement is a natural mediator of immunosurveillance, which can be compromised by locally sustained ligand expression but potentially restored by innate immune activation.

Publication types

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

MeSH terms

  • 9,10-Dimethyl-1,2-benzanthracene
  • Animals
  • Carcinoma / etiology
  • Carcinoma / metabolism
  • Carcinoma / pathology
  • Cell Line, Tumor
  • Disease Susceptibility
  • Down-Regulation
  • Female
  • Immunologic Surveillance
  • Killer Cells, Natural / immunology*
  • Ligands
  • Male
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • NK Cell Lectin-Like Receptor Subfamily K
  • Papilloma / etiology
  • Papilloma / metabolism
  • Papilloma / pathology
  • Receptors, Immunologic / immunology*
  • Receptors, Immunologic / metabolism*
  • Receptors, Natural Killer Cell
  • Skin Neoplasms / etiology
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology
  • T-Lymphocytes / immunology
  • Tetradecanoylphorbol Acetate
  • Tumor Burden


  • KLRK1 protein, human
  • Klrk1 protein, mouse
  • Ligands
  • Membrane Proteins
  • NK Cell Lectin-Like Receptor Subfamily K
  • Raet1a protein, mouse
  • Receptors, Immunologic
  • Receptors, Natural Killer Cell
  • 9,10-Dimethyl-1,2-benzanthracene
  • Tetradecanoylphorbol Acetate