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

Author

Listed:
  • Stephan Gasser

    (University of California)

  • Sandra Orsulic

    (Harvard Medical School)

  • Eric J. Brown

    (University of Pennsylvania School of Medicine)

  • David H. Raulet

    (University of California)

Abstract

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 mechanisms1. 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 kinases2. 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.

Suggested Citation

  • Stephan Gasser & Sandra Orsulic & Eric J. Brown & David H. Raulet, 2005. "The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor," Nature, Nature, vol. 436(7054), pages 1186-1190, August.
  • Handle: RePEc:nat:nature:v:436:y:2005:i:7054:d:10.1038_nature03884
    DOI: 10.1038/nature03884
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    Cited by:

    1. Jun Dai & Shuyu Zheng & Matías M. Falco & Jie Bao & Johanna Eriksson & Sanna Pikkusaari & Sofia Forstén & Jing Jiang & Wenyu Wang & Luping Gao & Fernando Perez-Villatoro & Olli Dufva & Khalid Saeed & , 2024. "Tracing back primed resistance in cancer via sister cells," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Buse Eglenen-Polat & Ryan R. Kowash & Hai-Cheng Huang & Silvia Siteni & Mingrui Zhu & Kenian Chen & Matthew E. Bender & Ilgen Mender & Victor Stastny & Benjamin J. Drapkin & Prithvi Raj & John D. Minn, 2024. "A telomere-targeting drug depletes cancer initiating cells and promotes anti-tumor immunity in small cell lung cancer," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Rosanna La Rocca & Rossana Tallerico & Almosawy Talib Hassan & Gobind Das & Lakshmikanth Tadepally & Marco Matteucci & Carlo Liberale & Maria Mesuraca & Domenica Scumaci & Francesco Gentile & Gheorghe, 2014. "Mechanical Stress Downregulates MHC Class I Expression on Human Cancer Cell Membrane," PLOS ONE, Public Library of Science, vol. 9(12), pages 1-20, December.
    4. Romain Marlin & Marion Duriez & Nadia Berkane & Claire de Truchis & Yoann Madec & Marie-Anne Rey-Cuille & Jean-Saville Cummings & Claude Cannou & Heloise Quillay & Françoise Barré-Sinoussi & Marie-Thé, 2012. "Dynamic Shift from CD85j/ILT-2 to NKG2D NK Receptor Expression Pattern on Human Decidual NK during the First Trimester of Pregnancy," PLOS ONE, Public Library of Science, vol. 7(1), pages 1-9, January.

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