The role of Tyrosine kinase 2 in a murine model of allergic asthma (139.9)

Abstract

Abstract Tyrosine Kinase 2 is a member of the mammalian Janus kinase (JAK) family of protein tyrosine kinases which consists of three more kinases (JAK1-3). Tyk-2 mutation in humans is associated with a completely defective in signaling in response to IFNα and IL-12, abnormal responses to IL-6, IL-10 and IL-23, susceptibility to viral infection and to mycobacterial infection and Hyper IgE Syndrome. Microscopic analyses showed that asthmatic Tyk2(-/-) mice suffered from extreme airway eosinophilic inflammation as compared to wild type mice. We found that Th1 differentiation is severely impaired in Tyk2(-/-) mice as shown by decreased IFNγ production by lung CD4+ T cells. By contrast, an increase in Th2 cytokines could be measured in the supernatants of lung CD4+ T cells isolated from Tyk2(-/-) mice. Preliminary results on T regulatory cell differentiation revealed an ascent of CD4+CD25+Foxp-3+ T regulatory cells in asthmatic Tyk2(-/-) mice by FACS analysis. Consistent with this finding, quantitative Real-Time PCR also showed an increase of the T regulatory cell-specific transcription factor Foxp3 in Tyk2(-/-) mice. As both the T regulatory inducing IL-10-pathway and the T reg inhibiting IL-6-pathway are blocked in Tyk2 deficient mice only TGFβ might be regulating Foxp-3 expression in T regulatory cells in these mice. We next wish to investigate the suppressive function of T regulatory cells in the absence of Tyk-2 in allergic models of asthma. This work is supported by Graduiertenkolleg 1043 "Antigen-specific Immunotherapy".