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<lom:entry>
  
<lom:langstring xml:lang="x-none">10.1007/s00018-025-05625-9</lom:langstring>

  
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</lom:identifier>

  
<lom:title>
  
<lom:langstring xml:lang="en">Cell-type-specific requirement for TYK2 in murine immune cells under steady state and challenged conditions</lom:langstring>

  
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<lom:description>
  
<lom:langstring xml:lang="en">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.</lom:langstring>

  
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<lom:language>eng</lom:language>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">Animals</lom:langstring>

  
</lom:keyword>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">TYK2 Kinase Metabolism</lom:langstring>

  
</lom:keyword>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">TYK2 Kinase Genetics</lom:langstring>

  
</lom:keyword>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">Mice</lom:langstring>

  
</lom:keyword>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">CD8-Positive T-Lymphocytes Immunology</lom:langstring>

  
</lom:keyword>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">CD8-Positive T-Lymphocytes Metabolism</lom:langstring>

  
</lom:keyword>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">Mice, Inbred C57BL</lom:langstring>

  
</lom:keyword>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">Macrophages Metabolism</lom:langstring>

  
</lom:keyword>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">Macrophages Immunology</lom:langstring>

  
</lom:keyword>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">Spleen Metabolism</lom:langstring>

  
</lom:keyword>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">Spleen Cytology</lom:langstring>

  
</lom:keyword>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">Killer Cells, Natural Immunology</lom:langstring>

  
</lom:keyword>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">Killer Cells, Natural Metabolism</lom:langstring>

  
</lom:keyword>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">Signal Transduction</lom:langstring>

  
</lom:keyword>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">Mice, Knockout</lom:langstring>

  
</lom:keyword>

  
<lom:keyword>
  
<lom:langstring xml:lang="en">Transcriptome</lom:langstring>

  
</lom:keyword>

  
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<lom:datetime>2025-04-03T07:56:20.708Z</lom:datetime>

  
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VERSION:3.0
N:Karjalainen;Anzhelika;
FN:Anzhelika Karjalainen
END:VCARD</lom:vcard>

  
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N:Witalisz-Siepracka;Agnieszka;
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N:Prchal-Murphy;Michaela;
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N:Martin;David;
FN:David Martin
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N:Sternberg;Felix;
FN:Felix Sternberg
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N:Krunic;Milica;
FN:Milica Krunic
END:VCARD</lom:vcard>

  
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N:Dolezal;Marlies;
FN:Marlies Dolezal
END:VCARD</lom:vcard>

  
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N:Fortelny;Nikolaus;
FN:Nikolaus Fortelny
END:VCARD</lom:vcard>

  
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<lom:centity>
  
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N:Farlik;Matthias;
FN:Matthias Farlik
END:VCARD</lom:vcard>

  
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N:Macho-Maschler;Sabine;
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<lom:centity>
  
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N:Lassnig;Caroline;
FN:Caroline Lassnig
X-ORCID:https://orcid.org/0000-0001-7905-3620
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VERSION:3.0
N:Meissl;Katrin;
FN:Katrin Meissl
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N:Amenitsch;Lena;
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N:Lederer;Therese;
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N:Pohl;Elena;
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N:Gotthardt;Dagmar;
FN:Dagmar Gotthardt
END:VCARD</lom:vcard>

  
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N:Bock;Christoph;
FN:Christoph Bock
END:VCARD</lom:vcard>

  
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VERSION:3.0
N:Decker;Thomas;
FN:Thomas Decker
END:VCARD</lom:vcard>

  
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<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Strobl;Birgit;
FN:Birgit Strobl
X-ORCID:https://orcid.org/0000-0001-5716-3212
END:VCARD</lom:vcard>

  
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<lom:vcard>BEGIN:VCARD
VERSION:3.0
N:Müller;Mathias;
FN:Mathias Müller
X-ORCID:https://orcid.org/0000-0002-7879-3552
END:VCARD</lom:vcard>

  
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