The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor

Nature. 2005 Aug 25;436(7054):1186-90. doi: 10.1038/nature03884. Epub 2005 Jul 3.


Some stimulatory receptors of the innate immune system, such as the NKG2D receptor (also called KLRK1) expressed by natural killer cells and activated CD8(+)T cells, recognize self-molecules that are upregulated in diseased cells by poorly understood mechanisms. Here we show that mouse and human NKG2D ligands are upregulated in non-tumour cell lines by genotoxic stress and stalled DNA replication, conditions known to activate a major DNA damage checkpoint pathway initiated by ATM (ataxia telangiectasia, mutated) or ATR (ATM- and Rad3-related) protein kinases. Ligand upregulation was prevented by pharmacological or genetic inhibition of ATR, ATM or Chk1 (a downstream transducer kinase in the pathway). Furthermore, constitutive ligand expression by a tumour cell line was inhibited by targeting short interfering RNA to ATM, suggesting that ligand expression in established tumour cells, which often harbour genomic irregularities, may be due to chronic activation of the DNA damage response pathway. Thus, the DNA damage response, previously shown to arrest the cell cycle and enhance DNA repair functions, or to trigger apoptosis, may also participate in alerting the immune system to the presence of potentially dangerous cells.

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

  • Animals
  • Aphidicolin / pharmacology
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / metabolism
  • Checkpoint Kinase 1
  • DNA Damage* / drug effects
  • DNA Replication / drug effects
  • Fibroblasts
  • Humans
  • Immune System / metabolism*
  • Immunity, Innate / physiology*
  • Kinetics
  • Ligands
  • Mice
  • Mice, Inbred C57BL
  • NK Cell Lectin-Like Receptor Subfamily K
  • Phosphorylation
  • Protein Kinases / metabolism
  • Protein Serine-Threonine Kinases / metabolism
  • Receptors, Immunologic / metabolism*
  • Receptors, Natural Killer Cell
  • Up-Regulation* / drug effects


  • Cell Cycle Proteins
  • KLRK1 protein, human
  • Klrk1 protein, mouse
  • Ligands
  • NK Cell Lectin-Like Receptor Subfamily K
  • Receptors, Immunologic
  • Receptors, Natural Killer Cell
  • Aphidicolin
  • Protein Kinases
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Chek1 protein, mouse
  • Protein Serine-Threonine Kinases