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 tumor-produced TNF-α. 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 high-affinity 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. •A mouse model of A-T, Atm−/−, develops T cell but not NK cell deficiency.•NK cell cytotoxicity is impaired in Atm−/− mice due to an early signaling block.•Ligands for the NKG2D receptor are expressed on T-cell precursors in Atm−/− mice.•NKG2D is down-regulated on NK cells of Atm−/− mice with MULT1+ thymic lymphoma.•Atm−/− NK cells become hyper-responsive upon development of TNF-α-expressing thymoma.