Severe combined immunodeficiency in stimulator of interferon genes (STING) V154M/wild-type mice - 06/08/18

Doi : 10.1016/j.jaci.2018.04.034

Delphine Bouis, PharmD, MSc ^a, Peggy Kirstetter, PhD ^b,^c,^d, Florent Arbogast, MSc ^a,^e, Delphine Lamon, TA ^a, Virginia Delgado, PhD ^a, Sophie Jung, DDS, PhD ^a,^f, Claudine Ebel, GE ^b,^c,^d, Hugues Jacobs, PhD ^b,^c,^d,^g,^h, Anne-Marie Knapp, GE ^a,ⁱ, Nadia Jeremiah, PhD ^j, Alexandre Belot, MD, PhD ^k,^l, Thierry Martin, MD, PhD ^a,^i,^m, Yanick J. Crow, MD, PhD ^n,^o,^p, Isabelle André-Schmutz, PhD ^o,^q, Anne-Sophie Korganow, MD, PhD ^a,^i,^m, Frédéric Rieux-Laucat, PhD ^o,^r, Pauline Soulas-Sprauel, PharmD, PhD ^a,^m,^s,^⁎
^a CNRS UPR 3572 “Immunopathology and Therapeutic Chemistry”/Laboratory of Excellence Medalis, Institute of Molecular and Cellular Biology (IBMC), Strasbourg, France
^b Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France
^c Institut National de la Santé et de la Recherche Médicale (INSERM), U964, Illkirch, France
^d Université de Strasbourg, Illkirch, France
^e UFR Sciences de la Vie, Université de Strasbourg, Strasbourg, France
^f Hôpitaux Universitaires de Strasbourg, Pôle de Médecine et de Chirurgie Bucco-dentaires, Centre de référence des maladies rares orales et dentaires (O'Rares) et Université de Strasbourg, Faculté de Chirurgie Dentaire, Strasbourg, France
^g Centre National de Recherche Scientifique (CNRS), UMR7104, Illkirch, France
^h CELPHEDIA, PHENOMIN, Institut Clinique de la Souris (ICS), Illkirch-Graffenstaden, France
ⁱ UFR Médecine, Université de Strasbourg, Strasbourg, France
^j Immunity and Cancer Department, Institut Curie, PSL Research University, INSERM U932, Paris, France
^k Service de Néphrologie, Rhumatologie, Dermatologie pédiatriques, Centre de référence RAISE, HFME, Hospices Civils de Lyon, Lyon, France
^l INSERM UMR 1111, Université de Lyon, Lyon, France
^m Department of Clinical Immunology and Internal Medicine, National Reference Center for Autoimmune Diseases, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
ⁿ INSERM UMR 1163, Laboratory of Neurogenetics and Neuroinflammation, Paris, France
^o Paris Descartes−Sorbonne Paris Cité University, Imagine Institute, Paris, France
^p Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
^q Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France
^r Laboratory of Immunogenetics of Pediatric autoimmune Diseases, INSERM UMR 1163, Paris, France
^s UFR Sciences Pharmaceutiques, Université de Strasbourg, Illkirch-Graffenstaden, France

^∗Corresponding author: Pauline Soulas-Sprauel, PharmD, PhD, CNRS UPR 3572 “Immunopathology and Therapeutic Chemistry,” Institute of Molecular and Cellular Biology (IBMC), 15 rue René Descartes, 67084 Strasbourg Cedex, France.CNRS UPR 3572 “Immunopathology and Therapeutic Chemistry,” Institute of Molecular and Cellular Biology (IBMC)15 rue René DescartesStrasbourg Cedex67084France

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Abstract

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.

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Key words : Severe combined immunodeficiency, stimulator of interferon genes, V154M, type I interferon

Abbreviations used : APC, BM, BrdU, cGAMP, CLP, DD, DN, ER, FITC, GOF, HSC, IFNAR, ILC, ISG, KO, LN, LT, NK, PE, SAVI, SCID, STING, TBK1, Treg, WT

Plan

Supported by grants from Strasbourg University (UdS), Centre National de la Recherche Scientifique (CNRS); Agence Nationale de la Recherche (ANR-14-CE14-0026-04, Lumugene; and ANR-11-EQPX-022); and the European Union–funded (ERDF) project INTERREG V “RARENET.” D.B. and F.A. were supported by Ministère de la Recherche et de la Technologie. V.D. was supported by Initiative of Excellence (IdEx), Strasbourg University, France. Y.J.C. acknowledges fellowship support from the European Research Council (GA 309449).

Disclosure of potential conflict of interest: A. Belot, Y. J. Crow, F. Rieux-Laucat, and P. Soulas-Sprauel are all collaborators in a project funded by the National Research Agency (ANR; no. ANR-14-CE14-0026-01, Lumugene). T. Martin, A.-S. Korganow, and P. Soulas-Sprauel received grants from the INTEREG program (EU-funded [ERDF] project INTERREG V “RARENET”). F. Rieux-Laucat received grants from Sanofi for the study of activating TMEM173 mutations in human subjects, a project that is not directly linked to this manuscript. The rest of the authors declare that they have no relevant conflicts of interest.