Tyrosine Kinase 2 Signalling Drives Pathogenic T cells in Colitis

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 [TYK2(KE)] were used to confirm selectivity of the inhibitor. To this end, RAG1(-/-) or RAG1(-/-)TYK2(KE) animals were transferred with either wild type [WT] or TYK2(KE)-CD45RB(high) 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 WTT cells into RAG(-/-)TYK2(KE) hosts induced colitis, TYK2(KE) T cells transferred into RAG1(-/-)TYK2(KE) recipients failed to do so. Ex vivo analysis showed a decrease in colon tissue Th1 cells and an increase in Th17 cells upon transfer of TYK2(KE)-CD45RB(high) 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.

Automated summary

The study investigates the role of TYK2 and its inhibitor TYK2i in experimental colitis. TYK2i effectively alleviates symptoms of colitis in mice, while T cells with TYK2 kinase activity deficiency also exhibit similar effects. The differentiation of human Th1 cells is also affected by TYK2i.