Absence of ATM leads to altered NK cell function in mice

Ataxia-telangiectasia (A -T) is a rare disorder caused by genetic defects of A -T mutated (ATM) kinase, a key regulator of stress response, and characterized by neurodegeneration, immunodeficiency, and high incidence of cancer. Here we investigated NK cells in a mouse model of A -T ( Atm - / - ) showing that they are strongly impaired at killing tumor cells due to a block of early signaling events. On the other hand, in Atm - / - littermates with thymic lymphoma NK cell cytotoxicity is enhanced as compared with ATM-proficient mice, possibly via tumorproduced TNF- alpha. Results also suggest that expansion of exhausted NKG2D + NK cells in Atm - / - mice is driven by low-level expression of stress-inducible NKG2D ligands, whereas development of thymoma expressing the highaffinity MULT1 ligand is associated with NKG2D down-regulation on NK cells. These results expand our understanding of immunodeficiency in A -T and encourage exploring NK cell biology in A -T patients in the attempt to identify cancer predictive biomarkers and novel therapeutic targets.