https://phaidra.vetmeduni.ac.at/o:4002 Cell-type-specific requirement for TYK2 in murine immune cells under steady state and challenged conditions Karjalainen, Anzhelika Anzhelika Karjalainen University of Veterinary Medicine Vienna Witalisz-Siepracka, Agnieszka Agnieszka Witalisz-Siepracka 0000-0003-0237-0745 University of Veterinary Medicine Vienna Prchal-Murphy, Michaela Michaela Prchal-Murphy University of Veterinary Medicine Vienna Martin, David David Martin University of Veterinary Medicine Vienna Sternberg, Felix Felix Sternberg University of Veterinary Medicine Vienna Krunic, Milica Milica Krunic Dolezal, Marlies Marlies Dolezal University of Veterinary Medicine Vienna Fortelny, Nikolaus Nikolaus Fortelny Farlik, Matthias Matthias Farlik Macho-Maschler, Sabine Sabine Macho-Maschler University of Veterinary Medicine Vienna Lassnig, Caroline Caroline Lassnig 0000-0001-7905-3620 University of Veterinary Medicine Vienna Meissl, Katrin Katrin Meissl University of Veterinary Medicine Vienna Amenitsch, Lena Lena Amenitsch 0000-0003-4873-1155 University of Veterinary Medicine Vienna Lederer, Therese Therese Lederer 0000-0001-7717-4111 University of Veterinary Medicine Vienna Pohl, Elena Elena Pohl 0000-0002-0604-5950 University of Veterinary Medicine Vienna Gotthardt, Dagmar Dagmar Gotthardt Bock, Christoph Christoph Bock Decker, Thomas Thomas Decker Strobl, Birgit Birgit Strobl 0000-0001-5716-3212 University of Veterinary Medicine Vienna Müller, Mathias Mathias Müller 0000-0002-7879-3552 University of Veterinary Medicine Vienna Springer journal article open access 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. 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 http://creativecommons.org/licenses/by/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:4002/download 10.1007/s00018-025-05625-9 https://phaidra.vetmeduni.ac.at/o:605 application/pdf Cellular and Molecular Life Sciences issn:1420-9071 VoR Cellular and Molecular Life Sciences 82 1 7.64 MB 2025