The role of Tyrosine kinase 2 on Th17 development in a murine model of allergic asthma (141.7)

Abstract

Abstract Mutations of the Janus Kinase Tyrosine Kinase 2 (Tyk2) in humans are associated with hypereosinophilia, Hyper-IgE and susceptibility to viral and mycobacterial infections. This syndrome was found to be the result of defective signaling of both IL 12 and IFNalpha as well as abnormal responses to IL 6, IL-10 and IL-23. Here we describe asthmatic Tyk2 deficient mice suffered from extreme airway eosinophilic inflammation and hyper IgE production compared to wild type mice. As these symptoms are associated with an increase in Th2 cytokines IL-4 and IL-5 in the airways, the major goal of the project is to investigate the role of Tyk2 in CD4+ T cell subset differentiation in the lung in a murine model of acute asthma. Th2 and early Th17 effector T cells are important in establishing the inflammation seen in the airways in this disease. In contrast, regulatory T cells and late developed Th17 T cells have a protective function on it. Under Th17 skewing conditions naïve CD4+ T cells from Tyk2 deficient mice showed an IL-6-dependent defect on Th17 cell development. Consistently, we found hyper-proliferation of Th2 cells associated with a constitutive inhibition of the Th1 and Th17 pathway in the lung of asthmatic Tyk2 deficient mice compared to wild type mice. In summary these data suggest that overexpression of Tyk2 could lead to amelioration of the asthmatic symptoms because this would suppress the pathogenic disease-specific CD4+ T effector cells in the lung.