We used conditional ablation of TYK2 in mice and showed that TYK2 promotes NK cell activity in tumour surveillance and the defence against Listeria monocytogenes infection through cell-extrinsic and -intrinsic mechanisms. The key discoveries are as follows: NK cell-extrinsic TYK2 drives peripheral NK cell maturation, demethylation of the Ifng locus, activating receptor-induced IFNg production, cytotoxicity and anti-tumour activity; the NK cell defects observed in Tyk2-/- mice can be restored by recombinant IL-15/IL-15Rα treatment; NK cell-intrinsic TYK2 signalling mediates infection-induced IFNg production and acts protective during Listeria monocytogenes infection.
Collectively, our study disclosed TYK2 functions that remained unrecognized in mice with complete TYK2 deficiency. Our findings that cytotoxic defects of Tyk2-/- NK cells can be rescued by IL-15/IL-15Rα treatment suggest that unwanted effects of TYK2 inhibitors in tumour therapy may be overcome by boosting NK cell activity.
Publication in Journal of Immunology
Natalija Simonović * , Agnieszka Witalisz-Siepracka *, Katrin Meissl, Caroline Lassnig, Ursula Reichart, Thomas Kolbe, Matthias Farlik, Christoph Bock, Veronika Sexl, Mathias Müller, and Birgit Strobl
*equal author contribution
NK Cells Require Cell-Extrinsic and -Intrinsic TYK2 for Full Functionality in Tumor Surveillance and Antibacterial Immunity (2019); Doi: