NK cells require cell-extrinsic and -intrinsic TYK2 for full functionality in tumor surveillance and antibacterial immunity

Tyrosine kinase 2 (TYK2) is a widely expressed receptor-associated kinase that is involved in signaling by a variety of cytokines with important immune regulatory activities. Absence of TYK2 in mice results in impaired NK cell maturation and antitumor activity, although underlying mechanisms are largely unknown. Using conditional ablation of TYK2 in NK cells we show that TYK2 is required for IFN-g production by NK cells in response to IL-12 and for an efficient immune defense against Listeria monocytogenes. Deletion of TYK2 in NK cells did not impact NKcellmaturation and IFN-g production upon NK cell activating receptor (actR) stimulation. Similarly, NK cell-mediated tumor surveillance was unimpaired upon deletion of TYK2 in NK cells only. In line with the previously reported maturation-associated Ifng promoter demethylation, the less mature phenotype of Tyk2 ^-/- NK cells correlated with an increased CpG methylation at the Ifng locus. Treatment with the DNA hypomethylating agent 5-aza-2-deoxycytidine restored the ability of Tyk2 ^-/- NK cells to produce IFN-g upon actR but not upon IL-12 stimulation. NK cell maturation was dependent on the presence of TYK2 in dendritic cells and could be rescued in Tyk2-deficient mice by treatment with exogenous IL-15/IL-15Ra complexes. IL-15 treatment also rescued the in vitro cytotoxicity defect and the impaired actR-induced IFN-g production of Tyk2 ^-/- NK cells. Collectively, our findings provide the first evidence, to our knowledge, for a key role of TYK2 in the host environment in promoting NK cell maturation and antitumor activity.