Tyrosine kinase 2 is not limiting human antiviral type III interferon responses.
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.
Center for Chronic Immunodeficiency, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany.
Sebastian
S
Fuchs
Professor-Hess-Kinderklinik, Bremen, Germany.
Petra
P
Kaiser-Labusch
Center for Chronic Immunodeficiency, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany.|Faculty of Biology, University of Freiburg, Germany.
Julia
J
Bank
Center for Chronic Immunodeficiency, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany.|Faculty of Biology, University of Freiburg, Germany.
Sandra
S
Ammann
Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
Anja
A
Kolb-Kokocinski
Department of General Pediatrics, University Children's Hospital Muenster, Münster, Germany.
Christine
C
Edelbusch
Department of General Pediatrics, University Children's Hospital Muenster, Münster, Germany.
Heymut
H
Omran
Center for Chronic Immunodeficiency, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany. stephan.ehl@uniklinik-freiburg.de.|Center for Pediatrics and Adolescent Medicine, Faculty of Medicine, Medical Center-University of Freiburg, Freiburg, Germany. stephan.ehl@uniklinik-freiburg.de.
Stephan
S
Ehl
D000818:Animals; D002460:Cell Line; D002648:Child; D004198:Disease Susceptibility / Q000276:immunology / Q000821:virology; D004485:Eczema / Q000209:etiology / Q000276:immunology; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007372:Interferons / Q000276:immunology*; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D007589:Job Syndrome / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D009154:Mutation; D018121:Receptors, Cytokine / Q000276:immunology; D053701:Receptors, Interleukin-10 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D012867:Skin / Q000473:pathology; D053634:TYK2 Kinase / Q000172:deficiency* / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D015850:Interleukin-6; D018121:Receptors, Cytokine; D053701:Receptors, Interleukin-10; D016753:Interleukin-10; D007073:Immunoglobulin E; D007371:Interferon-gamma; D007372:Interferons; D053634:TYK2 Kinase
HAP1 cells · IFN-lambda · Immunodeficiencies · NK cells · TYK2 · VSV-GFP