PRJNA759400
TYK2 protects from T cell-dependent liver injury through the induction IL-22
Tyrosine kinase 2 (TYK2) is a cytokine signal transducing kinase that emerged as promising target for the treatment of autoimmune and inflammatory diseases. Despite the increasing understanding of TYK2 signalling in diverse disease settings, its role in autoimmune hepatitis (AIH) is unknown. In this study we investigated the role of TYK2 in concanavalin A-induced hepatitis, a mouse model that mimics aspects of human T cell-mediated liver inflammation. We demonstrate that despite an impaired production of IFNg, which acts as a main driver of the disease, Tyk2-deficient mice show increased sensitivity to ConA-induced hepatitis compared to wild-type mice. Increased liver damage was due to an increase in liver cell apoptosis, but not necroptosis, and an impaired production of the hepatoprotective cytokine IL-22. Using adoptive transfer experiments and conditional knockout of Tyk2, we show that absence of TYK2 selectively in T cells, but not macrophages and neutrophils, suffices to increase the sensitivity to ConA-induced liver cell apoptosis and impairs the transcriptional upregulation of IL-22. Moreover, we show that treatment of Tyk2-deficient mice with a physiological dose of IL-22 rescues the increased sensitivity to ConA-induced liver damage. These results highlight the complex role of TYK2 in balancing protective and pathological immunity in various disease settings.