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NKG2D ligands mediate immunosurveillance of senescent cells

Adi Sagiv1, Dominick G A Burton1,2, Zhana Moshayev1

  • 1Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.

Aging
|February 17, 2016
PubMed

Insights

Cellular senescence triggers immune responses by up-regulating NKG2D ligands (MICA, ULBP2), enhancing Natural Killer (NK) cell killing of senescent cells. This interaction is crucial for preventing liver fibrosis.

Area of Science:

  • Immunology
  • Cell Biology
  • Gastroenterology

Background:

  • Cellular senescence, a stress-induced state, limits tumor growth and tissue damage.
  • Senescent cells often display an immunogenic phenotype, promoting their elimination by the immune system.
  • The precise mechanisms governing immune surveillance of senescent cells remain incompletely understood.

Purpose of the Study:

  • To investigate the regulation of immune ligand expression on senescent cells.
  • To elucidate the role of Natural Killer (NK) cell receptor NKG2D ligands in senescent cell recognition and elimination.
  • To determine the impact of NKG2D-ligand interactions on liver fibrosis.

Main Methods:

  • Induction of cellular senescence via replicative, oncogenic, and DNA damage pathways.
  • Analysis of NKG2D ligand (MICA, ULBP2) expression in senescent cells.
  • Assessment of NK cell-mediated cytotoxicity against senescent fibroblasts.
  • Investigation of signaling pathways (DNA damage response, ERK) regulating ligand expression.
  • Evaluation of liver fibrosis in mice lacking the NKG2D receptor.

Main Results:

  • MICA and ULBP2 ligands are consistently upregulated on senescent cells induced by various stressors.
  • MICA and ULBP2 are essential for NK cell-mediated killing of senescent fibroblasts.
  • Initial NKG2D ligand expression depends on DNA damage response, while sustained expression involves the ERK pathway.
  • Mice deficient in NKG2D exhibit increased senescent cell accumulation and exacerbated liver fibrosis.

Conclusions:

  • NKG2D ligands (MICA, ULBP2) are key regulators of immune recognition and clearance of senescent cells.
  • The interplay between DNA damage response, ERK signaling, and NKG2D ligand expression dictates immune surveillance.
  • NKG2D receptor-ligand interactions play a critical protective role against the development of liver fibrosis.
Keywords:
DNA damage responseERKNKG2DNatural Killer Cellfibrosissenescence

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