doi:10.1007/s00018-025-05625-9 eng Tyrosine kinase 2 (TYK2) deficiency and loss or inhibition of kinase activity in men and mice leads to similar immune compromised phenotypes, predominantly through impairment of interferon (IFN) and interleukin 12 family responses. Here we relate the transcriptome changes to phenotypical changes observed in TYK2-deficient (Tyk2-/-) and TYK2 kinase-inactive (Tyk2K923E) mice in naïve splenic immune cells and upon ex vivo IFN treatment or in vivo tumor transplant infiltration. The TYK2 activities under homeostatic and both challenged conditions are highly cell-type-specific with respect to quantity and quality of transcriptionally dependent genes. The major impact of loss of TYK2 protein or kinase activity in splenic homeostatic macrophages, NK and CD8+ T cells and tumor-derived cytolytic cells is on IFN responses. While reportedly TYK2 deficiency leads to partial impairment of IFN-I responses, we identified cell-type-specific IFN-I-repressed gene sets completely dependent on TYK2 kinase activity. Reported kinase-inactive functions of TYK2 relate to signaling crosstalk, metabolic functions and cell differentiation or maturation. None of these phenotypes relates to respective enriched gene sets in the TYK2 kinase-inactive cell types. Nonetheless, the scaffolding functions of TYK2 are capable to change transcriptional activities at single gene levels and chromatin accessibility at promoter-distal regions upon cytokine treatment most prominently in CD8+ T cells. The cell-type-specific transcriptomic and epigenetic effects of TYK2 shed new light on the biology of this JAK family member and are relevant for current and future treatment of autoimmune and inflammatory diseases with TYK2 inhibitors. Cell-type-specific requirement for TYK2 in murine immune cells under steady state and challenged conditions © 2025. The Author(s). open access application/pdf Text Wissenschaftlicher Artikel http://creativecommons.org/licenses/by/4.0/ 2025 Anzhelika Karjalainen Agnieszka Witalisz-Siepracka Michaela Prchal-Murphy David Martin Felix Sternberg Milica Krunic Marlies Dolezal Nikolaus Fortelny Matthias Farlik Sabine Macho-Maschler Caroline Lassnig Katrin Meissl Lena Amenitsch Therese Lederer Elena Pohl Dagmar Gotthardt Christoph Bock Thomas Decker Birgit Strobl Mathias Müller Animals TYK2 Kinase Metabolism TYK2 Kinase Genetics Mice CD8-Positive T-Lymphocytes Immunology CD8-Positive T-Lymphocytes Metabolism Mice, Inbred C57BL Macrophages Metabolism Macrophages Immunology Spleen Metabolism Spleen Cytology Killer Cells, Natural Immunology Killer Cells, Natural Metabolism Signal Transduction Mice, Knockout Transcriptome Text journal article Testo Articolo di rivista Springer Cellular and Molecular Life Sciences https://phaidra.vetmeduni.ac.at/o:4002