Tyrosine Kinase 2 Signalling Drives Pathogenic T cells in Colitis

Leonie C. S. de Vries, Mohammed Ghiboub, Patricia H. P. van Hamersveld, Olaf Welting, Caroline Verseijden, Matthew J. Bell, Inmaculada Rioja, Rabinder K. Prinjha, Pim J. Koelink, Birgit Strobl, Mathias Müller, Geert R. D'Haens, Manon E. Wildenberg, Wouter J. de Jonge

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8 Citations (Scopus)


BACKGROUND AND AIMS: Tyrosine kinase 2 [TYK2] is required for the signalling of key cytokines in the pathogenesis of inflammatory bowel disease [IBD]. We assessed the efficacy of a novel selective TYK2 inhibitor [TYK2i] in experimental colitis, using pharmacological and genetic tools. METHODS: At onset of T cell transfer colitis, RAG1-/- mice received vehicle or TYK2i daily by oral gavage. T cells lacking TYK2 kinase activity [TYK2KE] were used to confirm selectivity of the inhibitor. To this end, RAG1-/- or RAG1-/-TYK2KE animals were transferred with either wild type [WT] or TYK2KE-CD45RBhigh colitogenic T cells. Loss of body weight, endoscopic disease, the disease activity index [DAI], and histopathology scores were recorded. Tissues were analysed ex vivo for lymphocyte populations by flow cytometry. The impact of TYK2 inhibition on human DC-T cell interactions were studied using autologous Revaxis specific T cell assays. RESULTS: TYK2i [70 mg/kg] prevented weight loss and limited endoscopic activity during T cell transfer colitis. TYK2i [70 mg/kg] decreased DAI. Whereas transfer of WT T cells into RAG-/-TYK2KE hosts induced colitis, TYK2KE T cells transferred into RAG1-/-TYK2KErecipients failed to do so. Ex vivo analysis showed a decrease in colon tissue Th1 cells and an increase in Th17 cells upon transfer of TYK2KE-CD45RBhigh cells. In human antigen-triggered T cells, TYK2i displayed reduced Th1 differentiation, similar to murine Th1 cells. CONCLUSIONS: Oral administration of TYK2i, as well as transfer of T cells lacking TYK2 activity, reduced human Th1 differentiation and ameliorated the course of murine T cell transfer colitis. We conclude that TYK2 is a promising drug target for the treatment of IBD.
Original languageEnglish
Pages (from-to)617-630
Number of pages14
JournalJournal of Crohn's & Colitis
Issue number4
Early online date1 Oct 2020
Publication statusPublished - 6 Apr 2021


  • IBD
  • Janus kinase inhibitor
  • Tyrosine kinase 2 inhibitor
  • experimental colitis

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