Identifying Diseased Cells

Science's STKE  30 Aug 2005:
Vol. 2005, Issue 299, pp. tw310
DOI: 10.1126/stke.2992005tw310

Tumors and virus-infected cells express cell surface molecules that act as ligands for NKG2D, an activating receptor found on natural killer (NK) cells and CD8+ T cells, thereby targeting the diseased cells for an immune response. Gasser et al. found that two transformed ovarian epithelial cell lines from mice lacking p53, C1 (transduced with K-ras and c-myc), and C2 (transduced with Akt and c-myc) did not express appreciable quantities of NKG2D ligands. Cell lines derived from ovarian tumors that were generated in mice from the C1 or C2 lines, however, showed substantial ligand abundance. Although various stressors (heat shock, hyperoxia, hypoxia, inflammatory cytokines, acidic or alkaline media, cell cycle inhibition) failed to affect NKG2D ligand abundance in C1 or C2 cells, DNA-damaging agents and DNA synthesis inhibitors increased NKG2D ligand abundance in C1 and C2 cells and in mouse and human fibroblasts. All of the treatments that effectively stimulated NKG2D ligand expression are known to trigger the DNA damage checkpoint pathway initiated by ATM (ataxia telangiectasia, mutated) or ATR (ATM- and Rad3-related). The authors used pharmacological analysis, RNA interference, and conditional expression of Atr to implicate ATR and the downstream kinase Chk1 in the increase in NKG2D ligand abundance in response to the DNA polymerase inhibitor aphidocolin and to implicate ATM in the response to ionizing radiation and hypotonic conditions. Moreover, short interfering RNA (siRNA) directed against ATM reduced the abundance of NKG2D ligands in the tumor cell line derived from C2. Thus, the authors propose that the DNA damage response may provide an unexpected link between loss of genomic integrity and activation of the immune response.

S. Gasser, S. Orsulic, E. J. Brown, D. H. Raulet, The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436, 1186-1190 (2005). [Online Journal]