Impact Statement
TYK2 deficiency is a rare primary immunodeficiency disease caused by loss of function mutations of TYK2 gene. Due to rarely reported cases, the nature of TYK2 deficiency and the function of TYK2 in human immune system are poorly understood. This study describes five TYK2 deficient cases presenting with or without hyper IgE levels, atopy and distinct pathogen infection profiles, which are caused by novel TYK2 mutations. Peripheral blood mononulear cells (PBMCs) from these patients showed heterogenous responses to various cytokines treatment, including IFN-α/β/γ, IL-6, IL-10, IL12 and IL-23. The homeostasis of lymphocytes is also disrupted. Based on our findings, we propose that TYK2 works as a multi-tasker in orchestrating various cytokines signaling pathways, differentially combined defects of which account for the expressed clinical manifestations.