1. Severe combined immunodeficiency in stimulator of interferon genes (STING) V154M/wild-type mice
- Author
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Claudine Ebel, Anne-Marie Knapp, Virginia Delgado, Isabelle André-Schmutz, Anne-Sophie Korganow, Pauline Soulas-Sprauel, Delphine Bouis, Delphine Lamon, Nadia Jeremiah, Florent Arbogast, Peggy Kirstetter, Alexandre Belot, Thierry Martin, Frédéric Rieux-Laucat, Yanick J. Crow, Hugues Jacobs, Sophie Jung, CCSD, Accord Elsevier, Immunopathologie et chimie thérapeutique (ICT), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Les Hôpitaux Universitaires de Strasbourg (HUS), Institut Clinique de la Souris (ICS), Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Edinburgh, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
0301 basic medicine ,stimulator of interferon genes ,[SDV]Life Sciences [q-bio] ,T-Lymphocytes ,Immunology ,Receptor, Interferon alpha-beta ,Biology ,Natural killer cell ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Interferon ,Agammaglobulinemia ,Sciences du Vivant [q-bio]/Biologie cellulaire ,medicine ,Immunology and Allergy ,Animals ,Humans ,Sciences du Vivant [q-bio]/Immunologie ,Inflammation ,Mice, Knockout ,Severe combined immunodeficiency ,B-Lymphocytes ,Interferon-stimulated gene ,Wild type ,Membrane Proteins ,Cell Differentiation ,V154M ,medicine.disease ,eye diseases ,3. Good health ,[SDV] Life Sciences [q-bio] ,Killer Cells, Natural ,Mice, Inbred C57BL ,Sting ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Stimulator of interferon genes ,Knockout mouse ,Interferon Type I ,Mutation ,type I interferon ,Severe Combined Immunodeficiency ,030215 immunology ,medicine.drug - Abstract
International audience; Background: Autosomal dominant gain-of-function mutations in human stimulator of interferon genes (STING) lead to a severe autoinflammatory disease called STING-associated vasculopathy with onset in infancy that is associated with enhanced expression of interferon-stimulated gene transcripts.Objective: The goal of this study was to analyze the phenotype of a new mouse model of STING hyperactivation and the role of type I interferons in this system.Methods: We generated a knock-in model carrying an amino acid substitution (V154M) in mouse STING, corresponding to a recurrent mutation seen in human patients with STING-associated vasculopathy with onset in infancy. Hematopoietic development and tissue histology were analyzed. Lymphocyte activation and proliferation were assessed in vitro. STING V154M/wild-type (WT) mice were crossed to IFN-α/β receptor (IFNAR) knockout mice to evaluate the type I interferon dependence of the mutant Sting phenotype recorded.Results: In STING V154M/WT mice we detected variable expression of inflammatory infiltrates in the lungs and kidneys. These mice showed a marked decrease in survival and developed a severe combined immunodeficiency disease (SCID) affecting B, T, and natural killer cells, with an almost complete lack of antibodies and a significant expansion of monocytes and granulocytes. The blockade in B- and T-cell development was present from early immature stages in bone marrow and thymus. In addition, in vitro experiments revealed an intrinsic proliferative defect of mature T cells. Although the V154M/WT mutant demonstrated increased expression of interferon-stimulated genes, the SCID phenotype was not reversed in STING V154M/WT IFNAR knockout mice. However, the antiproliferative defect in T cells was rescued partially by IFNAR deficiency.Conclusions: STING gain-of-function mice developed an interferon-independent SCID phenotype with a T-cell, B-cell, and natural killer cell developmental defect and hypogammaglobulinemia that is associated with signs of inflammation in lungs and kidneys. Only the intrinsic proliferative defect of T cells was partially interferon dependent.
- Published
- 2017