title: NKG2D ligands mediate immunosurveillance of senescent cells.
abstract: 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.
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Adi
authors.initials: A
authors.lastname: Sagiv
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.|Present address: School of Life and Health Sciences, Aston University, Birmingham, UK.
authors.forename: Dominick G A
authors.initials: DG
authors.lastname: Burton
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Zhana
authors.initials: Z
authors.lastname: Moshayev
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Ezra
authors.initials: E
authors.lastname: Vadai
authors.affiliation: School of Medicine, University of Rijeka, Croatia.
authors.forename: Felix
authors.initials: F
authors.lastname: Wensveen
authors.affiliation: Bioinformatics and Biological Computing Unit, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Shifra
authors.initials: S
authors.lastname: Ben-Dor
authors.affiliation: Biological Services Department, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Ofra
authors.initials: O
authors.lastname: Golani
authors.affiliation: School of Medicine, University of Rijeka, Croatia.
authors.forename: Bojan
authors.initials: B
authors.lastname: Polic
authors.affiliation: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Valery
authors.initials: V
authors.lastname: Krizhanovsky
mesh_terms: D000818:Animals; D016922:Cellular Senescence / Q000276:immunology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007157:Immunologic Surveillance / Q000276:immunology*; D007694:Killer Cells, Natural; D008024:Ligands; D008103:Liver Cirrhosis / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology*
chemical_list: D008024:Ligands; D055655:NK Cell Lectin-Like Receptor Subfamily K
keywords: DNA damage response; ERK; NKG2D; Natural Killer Cell; fibrosis; senescence