Tyrosine kinase 2 is not limiting human antiviral type III interferon responses |
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| Authors: | Sebastian Fuchs Petra Kaiser‐Labusch Julia Bank Sandra Ammann Anja Kolb‐Kokocinski Christine Edelbusch Heymut Omran Stephan Ehl |
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| Affiliation: | 1. Center for Chronic Immunodeficiency, Faculty of Medicine, Medical Center—University of Freiburg, Freiburg, Germany;2. Professor‐Hess‐Kinderklinik, Bremen, Germany;3. Faculty of Biology, University of Freiburg, Germany;4. Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom;5. Department of General Pediatrics, University Children's Hospital Muenster, Münster, Germany;6. Center for Pediatrics and Adolescent Medicine, Faculty of Medicine, Medical Center—University of Freiburg, Freiburg, Germany |
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| Abstract: | Tyrosine kinase 2 (TYK2) associates with interferon (IFN) alpha receptor, IL‐10 receptor (IL‐10R) beta and other cytokine receptor subunits for signal transduction, in response to various cytokines, including type‐I and type‐III IFNs, IL‐6, IL‐10, IL‐12 and IL‐23. Data on TYK2 dependence on cytokine responses and in vivo consequences of TYK2 deficiency are inconsistent. We investigated a TYK2 deficient patient, presenting with eczema, skin abscesses, respiratory infections and IgE levels >1000 U/mL, without viral or mycobacterial infections and a corresponding cellular model to analyze the role of TYK2 in type‐III IFN mediated responses and NK‐cell function. We established a novel simple diagnostic monocyte assay to show that the mutation completely abolishes the IFN‐α mediated antiviral response. It also partly reduces IL‐10 but not IL‐6 mediated signaling associated with reduced IL‐10Rβ expression. However, we found almost normal type‐III IFN signaling associated with minimal impairment of virus control in a TYK2 deficient human cell line. Contrary to observations in TYK2 deficient mice, NK‐cell phenotype and function, including IL‐12/IL‐18 mediated responses, were normal in the patient. Thus, preserved type‐III IFN responses and normal NK‐cell function may contribute to antiviral protection in TYK2 deficiency leading to a surprisingly mild human phenotype. |
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| Keywords: | HAP1 cells · IFN‐lambda · Immunodeficiencies · NK cells · TYK2 · VSV‐GFP |
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