Tyrosine kinase 2 is not limiting human antiviral type III interferon responses. Issue 11 (5th October 2016)

• Record Type: Journal Article
• Authors: Fuchs, Sebastian; Kaiser‐Labusch, Petra; Bank, Julia; Ammann, Sandra; Kolb‐Kokocinski, Anja; Edelbusch, Christine; Omran, Heymut; Ehl, Stephan
• Is Part Of: European journal of immunology. Volume 46:Issue 11(2016)
• Page Start: 2639
• Page End: 2649
• Publication Date: 2016-10-05
• Subjects: HAP1 cells · IFN‐lambda · Immunodeficiencies · NK cells · TYK2 · VSV‐GFP; Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201646519
• Languages: English
• ISSNs: 0014-2980

Abstract

Abstract : IFN‐λ mediated signal transduction is functionally retained in TYK2 deficient human cell lines. This, together with functional NK cell responses in vitro, might account for the absence of severe viral infections in patients with TYK2 deficiency despite the lack of IFN‐α mediated signal transduction. 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.