NK Cells Require Cell-Extrinsic and -Intrinsic TYK2 for Full Functionality in Tumor Surveillance and Antibacterial Immunity

Abstract

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 NK cell maturation 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 2/2 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 2/2 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 2/2 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.

TYK2 in Tumor Immunosurveillance

“…The high susceptibility of Tyk2 −/− mice to lymphoid tumors is the result of an impaired tumor surveillance, in particular, a decreased cytotoxic capacity of NK/NKT and CTL cells [86,98]. The importance of TYK2 for NK cell-and CD8 + T cell-targeted tumor growth restriction was confirmed by studies with local tumor transplant models, using lymphoma (RMA-S and RMA-Rae1) and adenocarcinoma (MC38) cells [67,76,93]. Reduced CTL-dependent tumor cell killing is linked to impaired type I IFN signaling, although the mechanisms are elusive [98].…”

“…IL-15 is dynamically regulated in the TME and enhances anti-tumor immunity [227,229,230]. We have shown that the absence of TYK2 in DCs results in reduced levels of IL-15Rα on DCs and macrophages in naïve mice ( [93] and see below). However, the nature of the TYK2-dependent signals that drive IL-15/IL-15Rα expression under homeostatic conditions is unclear.…”

“…The work also implicates TYK2 in the regulation of IL-15Rα on CD11c + cells but not NK cells or T cells. Administration of exogenous IL-15/IL-15Rα to Tyk2-deficient mice restores NK-cell maturation and NK cell-dependent control of tumor growth [93]. In contrast to the situation in NK cells, the CTL-dependent restriction of locally transplanted tumors is independent of TYK2 in myeloid cells and DCs [67].…”

“…Mutations in IFNγ pathway genes underlie resistance to immune checkpoint therapies, i.e., block of PD1/PD-L1 or CTL4-A [236][237][238]. We and others have established that IL-12-or IL-23-activated TYK2 is central to the production of IFNγ during immunity to tumors and to infections as well as during inflammation ( [52,61,93] and see Table 2).…”

“…Defective NK cell-dependent tumor growth control in the absence of TYK2 correlates with defects in splenic NK-cell maturation; NK-cell development in the bone marrow is independent of TYK2 [76]. Studies with conditional knockout mice have shown that TYK2 in DCs (CD11c + ) and other non-NK cells, rather than in NK cells themselves, drives terminal NK cell maturation in the spleen [93]. The work also implicates TYK2 in the regulation of IL-15Rα on CD11c + cells but not NK cells or T cells.…”