NKG2D ligands mediate immunosurveillance of senescent cells


Cellular senescence is a stress response mechanism that limits tumorigenesis and tissue damage. Induction of cellular senescence commonly coincides with an immunogenic phenotype that promotes self-elimination by components of the immune system, thereby facilitating tumor suppression and limiting excess fibrosis during wound repair. The mechanisms by which senescent cells regulate their immune surveillance are not completely understood. Here we show that ligands of an activating Natural Killer (NK) cell receptor (NKG2D), MICA and ULBP2 are consistently up-regulated following induction of replicative senescence, oncogene-induced senescence and DNA damage - induced senescence. MICA and ULBP2 proteins are necessary for efficient NK-mediated cytotoxicity towards senescent fibroblasts. The mechanisms regulating the initial expression of NKG2D ligands in senescent cells are dependent on a DNA damage response, whilst continuous expression of these ligands is regulated by the ERK signaling pathway. In liver fibrosis, the accumulation of senescent activated stellate cells is increased in mice lacking NKG2D receptor leading to increased fibrosis. Overall, our results provide new insights into the mechanisms regulating the expression of immune ligands in senescent cells and reveal the importance of NKG2D receptor-ligand interaction in protecting against liver fibrosis.

Publication DOI: https://doi.org/10.18632/aging.100897
Divisions: College of Health & Life Sciences
College of Health & Life Sciences > School of Biosciences > Cell & Tissue Biomedical Research
Additional Information: Sagiv et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: Marie Curie RG grant; ERC EU’s FP7; and Israel Science Foundation
Uncontrolled Keywords: DNA damage response,ERK,fFibrosis,natural killer cells,NKG2D,senescence,Ageing,Cell Biology
Full Text Link: http://www.impa ... bs/100897a.html
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2016-02-13
Accepted Date: 2016-01-27
Submitted Date: 2015-12-18
Authors: Sagiv, Adi
Burton, Dominick G.A.
Moshayev, Zhana
Vadai, Ezra
Wensveen, Felix
Ben-Dor, Shifra
Golani, Ofra
Polic, Bojan
Krizhanovsky, Valery



Version: Published Version

License: Creative Commons Attribution

Export / Share Citation


Additional statistics for this record