NKG2D (natural-killer group 2, member D) is an activating receptor that is expressed at the surface of natural killer (NK) cells and CD8+ T cells. NKG2D recognizes ligands that are upregulated by diseased cells, leading to the lysis of these cells, but regulation of the expression of NKG2D ligands is poorly understood. In this study, the authors studied ovarian epithelial cell lines. NKG2D ligands were not expressed in culture by cells that had been transformed, as detected using an NKG2D tetramer, but they were expressed when the transformed cells were injected into the ovaries of mice and developed into tumours. So, transformation per se is not sufficient to induce upregulation of ligand expression.
Next, the authors subjected the transformed ovarian epithelial cells to various cellular stresses, including changes in pH, changes in oxygen concentration, and heat shock. However, the cells expressed NKG2D ligands only after exposure to ionizing radiation, inhibitors of DNA replication or chromatin-modifying reagents, all of which activate a major DNA-damage-response pathway that is initiated by the protein kinases ATM (ataxia telangiectasia mutated) and/or ATR (ATM- and RAD3-related). These treatments also induced NKG2D-ligand expression by normal adult fibroblasts. Other treatments, such as with ultraviolet light or the chemotherapeutic reagent cisplatin, also induced NKG2D-ligand expression by these fibroblasts. The role of ATR in upregulation of NKG2D-ligand expression was confirmed in three ways: by inhibiting ATR and ATM using caffeine, by blocking ATR expression using small interfering RNA and by showing that fibroblasts deficient in ATR could not upregulate expression of NKG2D ligands in response to genotoxic stress. Regulation of ligand expression did not depend on arrest of the cell cycle or on induction of cell-death pathways.
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