title: In vivotumor surveillance by NK cells requires TYK2 but not TYK2 kinase activity.
abstract: Tyrosine kinase 2 (TYK2) is a Janus kinase (JAK) that is crucially involved in inflammation, carcinogenesis and defense against infection. The cytotoxic activity of natural killer (NK) cells in TYK2-deficient (Tyk2-/-) mice is severely reduced, although the underlying mechanisms are largely unknown. UsingTyk2-/-mice and mice expressing a kinase-inactive version of TYK2 (Tyk2K923E), we show that NK cell function is partly independent of the enzymatic activity of TYK2.Tyk2-/-andTyk2K923ENK cells develop normally in the bone marrow, but the maturation of splenicTyk2-/-NK cells (and to a lesser extent ofTyk2K923ENK cells) is impaired. In contrast, the production of interferon γ (IFNγ) in response to interleukin 12 (IL-12) or to stimulation through NK cell-activating receptors strictly depends on the presence of enzymatically active TYK2. The cytotoxic activity ofTyk2K923ENK cells against a range of target cellsin vitrois higher than that ofTyk2-/-NK cells. Consistently,Tyk2K923Emice control the growth of NK cell-targeted tumors significantly better than TYK2-deficient mice, showing the physiological relevance of the finding. Inhibitors of TYK2's kinase activity are being developed for the treatment of inflammatory diseases and cancers, but their effects on tumor immune surveillance have not been investigated. Our finding that TYK2 has kinase-independent functionsin vivosuggests that such inhibitors will leave NK cell mediated tumor surveillance largely intact and that they will be suitable for use in cancer therapy.
authors.affiliation: Institute of Animal Breeding and Genetics; University of Veterinary Medicine ; Vienna, Austria ; Institute of Pharmacology and Toxicology; University of Veterinary Medicine ; Vienna, Austria.
authors.forename: Michaela
authors.initials: M
authors.lastname: Prchal-Murphy
authors.affiliation: Institute of Animal Breeding and Genetics; University of Veterinary Medicine ; Vienna, Austria.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Witalisz-Siepracka
authors.affiliation: Institute of Animal Breeding and Genetics; University of Veterinary Medicine ; Vienna, Austria.
authors.forename: Karoline T
authors.initials: KT
authors.lastname: Bednarik
authors.affiliation: Institute of Pharmacology and Toxicology; University of Veterinary Medicine ; Vienna, Austria.
authors.forename: Eva Maria
authors.initials: EM
authors.lastname: Putz
authors.affiliation: Institute of Pharmacology and Toxicology; University of Veterinary Medicine ; Vienna, Austria.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Gotthardt
authors.affiliation: Institute of Animal Breeding and Genetics; University of Veterinary Medicine ; Vienna, Austria.
authors.forename: Katrin
authors.initials: K
authors.lastname: Meissl
authors.affiliation: Institute of Pharmacology and Toxicology; University of Veterinary Medicine ; Vienna, Austria.
authors.forename: Veronika
authors.initials: V
authors.lastname: Sexl
authors.affiliation: Institute of Animal Breeding and Genetics; University of Veterinary Medicine ; Vienna, Austria ; Biomodels Austria; University of Veterinary Medicine ; Vienna, Austria.
authors.forename: Mathias
authors.initials: M
authors.lastname: Müller
authors.affiliation: Institute of Animal Breeding and Genetics; University of Veterinary Medicine ; Vienna, Austria.
authors.forename: Birgit
authors.initials: B
authors.lastname: Strobl
keywords: NK cells; interferon γ; interleukin-12; tumor surveillance; tyrosine kinase 2