Fine-tuning the reverse genetics of Tyk2
NETWORK CONTRIBUTION
The Janus kinase (Jak) Tyk2 is an important determinant in host immunity both in mice and in humans. Tyk2 deficiency results in increased sensitivity to microbial infections and increased tumor development but improves clinical symptoms in several autoimmune and inflammatory diseases. Tyk2 inhibitors are in development and are considered to be promising tools for the treatment of human diseases, including psoriasis, rheumatoid arthritis and inflammatory bowel disease. However, several lines of evidence suggest that Jaks may have kinase-independent activities, e.g. receptor stabilizing and adapter functions.
Our major goals are to dissect kinase-dependent and -independent functions of Tyk2 in vivo. During the previous funding periods we have generated mice that express a kinase-inactive Tyk2 protein (Tyk2K923E) and could confirm our hypothesis that the lack of Tyk2 kinase activity does not phenocopy Tyk2 deficiency. Unexpectedly, we found that kinase-inactive Tyk2 contributes to tumor surveillance and our results point towards an involvement of natural killer (NK) cells in the process. In contrast, Tyk2 kinase activity is essential for canonical type I interferon (IFNα/β) signaling and to control viral infections in vivo.
The most prominent defect in Tyk2-/- mice is impaired interleukin-12 (IL-12) signaling and a consequent failure to produce IFNγ upon a wide range of immunological challenges. This defect crucially contributes to both the increased sensitivity to infections and the resistance against inflammatory diseases. It may also account, at least partially, for the defective tumor surveillance observed in Tyk2-/- mice. IL-12 signaling is similarly impaired in Tyk2-/- and Tyk2K923E lymphocytes but surprisingly we found Tyk2 kinase-independent, delayed IFNγ production after Listeria monocytogenes infection in vivo.
Within the proposed project part we aim to determine how kinase-inactive Tyk2 contributes to NK cell activity and tumor surveillance. Furthermore, we aim at further dissecting kinase-dependent and -independent functions of Tyk2 in the regulation of IFN production and during innate and adaptive immune responses to L. monocytogenes infections.
CONTACT
Department of Biomedical Sciences, Institute of Animal Breeding and Genetics
University of Veterinary Medicine Vienna, Vetmeduni Vienna
A-1210 Vienna, Austria
HYPOTHESES
Kinase-inactive Tyk2 contributes to NK cell- but not CD8+ T cell-mediated tumor immune surveillance.
Kinase-dependent and -independent functions of Tyk2 control NK cell development/maturation and/or NK cell cytotoxicity.
The presence of kinase-inactive Tyk2 impairs innate IFNγ production but triggers alternative adaptive immune cell activation, or (b) kinase-inactive Tyk2 blocks negative immune regulatory pathways acting on IFNγ-producing cells.
Kinase-inactive Tyk2 can contribute to the control of low-dose L. monocytogenes infection and to the development of adaptive immunity.
PUBLICATIONS
TEAM
Mathias Müller
Marie T. Marcus
Eruditi postulant at vix, maiorum petentium ut quo, has id esse meis.
Jill T. Medeiros
Eruditi postulant at vix, maiorum petentium ut quo, has id esse meis.
Margaret K. James
Et aliquip pertinax ullamcorper sit, ad ius omnes placerat salutandi.
Fine-tuning the reverse genetics of Tyk2
NETWORK CONTRIBUTION
The Janus kinase (Jak) Tyk2 is an important determinant in host immunity both in mice and in humans. Tyk2 deficiency results in increased sensitivity to microbial infections and increased tumor development but improves clinical symptoms in several autoimmune and inflammatory diseases. Tyk2 inhibitors are in development and are considered to be promising tools for the treatment of human diseases, including psoriasis, rheumatoid arthritis and inflammatory bowel disease. However, several lines of evidence suggest that Jaks may have kinase-independent activities, e.g. receptor stabilizing and adapter functions.
Our major goals are to dissect kinase-dependent and -independent functions of Tyk2 in vivo. During the previous funding periods we have generated mice that express a kinase-inactive Tyk2 protein (Tyk2K923E) and could confirm our hypothesis that the lack of Tyk2 kinase activity does not phenocopy Tyk2 deficiency. Unexpectedly, we found that kinase-inactive Tyk2 contributes to tumor surveillance and our results point towards an involvement of natural killer (NK) cells in the process. In contrast, Tyk2 kinase activity is essential for canonical type I interferon (IFNα/β) signaling and to control viral infections in vivo.
The most prominent defect in Tyk2-/- mice is impaired interleukin-12 (IL-12) signaling and a consequent failure to produce IFNγ upon a wide range of immunological challenges. This defect crucially contributes to both the increased sensitivity to infections and the resistance against inflammatory diseases. It may also account, at least partially, for the defective tumor surveillance observed in Tyk2-/- mice. IL-12 signaling is similarly impaired in Tyk2-/- and Tyk2K923E lymphocytes but surprisingly we found Tyk2 kinase-independent, delayed IFNγ production after Listeria monocytogenes infection in vivo.
Within the proposed project part we aim to determine how kinase-inactive Tyk2 contributes to NK cell activity and tumor surveillance. Furthermore, we aim at further dissecting kinase-dependent and -independent functions of Tyk2 in the regulation of IFN production and during innate and adaptive immune responses to L. monocytogenes infections.
CONTACT
Department of Biomedical Sciences, Institute of Animal Breeding and Genetics
University of Veterinary Medicine Vienna, Vetmeduni Vienna
A-1210 Vienna, Austria
HYPOTHESES
Kinase-inactive Tyk2 contributes to NK cell- but not CD8+ T cell-mediated tumor immune surveillance.
Kinase-dependent and -independent functions of Tyk2 control NK cell development/maturation and/or NK cell cytotoxicity.
The presence of kinase-inactive Tyk2 impairs innate IFNγ production but triggers alternative adaptive immune cell activation, or (b) kinase-inactive Tyk2 blocks negative immune regulatory pathways acting on IFNγ-producing cells.
Kinase-inactive Tyk2 can contribute to the control of low-dose L. monocytogenes infection and to the development of adaptive immunity.
PUBLICATIONS
TEAM
Mathias Müller
Marie T. Marcus
Eruditi postulant at vix, maiorum petentium ut quo, has id esse meis.
Jill T. Medeiros
Eruditi postulant at vix, maiorum petentium ut quo, has id esse meis.
Margaret K. James
Et aliquip pertinax ullamcorper sit, ad ius omnes placerat salutandi.