Tyk2 deficient and Stat1 transgenic mice - Models for host pathogen interactions and cytokine networks

The Jak-Stat signalling cascade plays a role in a variety of cytokine cascades and in the host response to pathogens. Major positive regulating components of this pathway are the Jak family of receptor-associated tyrosine kinases and further downstream the family of signal transducers and transcription factors, Stats. The targeting of Tyk2 was the last of the Jak family members to be reported (Karaghiosoff et al., 2000, Immunity 13: 549-560). In contrast to the other Jaks, Tyk2 deficiency results in a differentiated response to particular cytokines, i.e. only partial and/or cell type specific impairment of most cytokine receptor functions. However, the cellular response to lipopolysaccharide is completely impaired, indicating a pivotal role of Tyk2 in this complex host response. Importantly, Tyk2 is not only required for full functional activation of the Stats, but also obligatory in the maintenance of Stat1 protein levels (Karaghiosoff et al., 2000, Immunity 13: 549-560). The aim of this project is to further elucidate the role of Tyk2 in the host response to various pathogens and networked cytokine stimuli. Looking at particular Tyk2 functions, some defects observed in Tyk2-/- mice could be influenced by the reduced Stat1 protein level. Our aim is to identify Tyk2-specific - Stat1-independent - functions in vivo by reconstituting normal Stat1 protein levels in Tyk2 deficient mice. This will be achieved by Stat1 transgenic (Stat1-TG) mice crossed to the Tyk2 null allele mice. We will generate Stat1-TG mice with the transgene being controlled in a strictly inducible manner using a novel synthetic non-mammalian expression system which allows transgene transcription only in the presence of an orally applicable dimerizer. The Stat1-TG/ Tyk2-/- mice will be analysed for Tyk2 functions in the host defence against viral and bacterial pathogens and in different cytokine cascades. Comparing the results with the original data of the Tyk2 deficient (not Stat1 reconstituted) mice we will be able to distinguish between the Tyk2- and Stat1-specific contribution in the analysed biological systems. To our knowledge, this project will generate the first model for Stat1 overexpression in transgenic mice.