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

Delphine Bouis (1) , Peggy Kirstetter (2) , Florent Arbogast (1) , Delphine Lamon (1) , Virginia Delgado (1) , Sophie Jung (1, 3) , Claudine Ebel (2) , Hugues Jacobs (2, 4) , Anne-Marie Knapp (1) , Nadia Jeremiah (5, 6) , Alexandre Belot (7, 8) , Thierry Martin (1, 3) , Yanick Crow (9, 10) , Isabelle André-Schmutz (9) , Anne-Sophie Korganow (1, 3) , Frédéric Rieux-Laucat (9) , Pauline Soulas-Sprauel (1, 3)

1 ICT - Immunopathologie et chimie thérapeutique
2 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
3 HUS - Les Hôpitaux Universitaires de Strasbourg
4 ICS - Institut Clinique de la Souris
5 U932 - Immunité et cancer
6 PSL - Université Paris Sciences et Lettres
7 CIRI - Centre International de Recherche en Infectiologie
8 HCL - Hospices Civils de Lyon
9 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
10 Edin. - University of Edinburgh

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.

Mots clés: Severe combined immunodeficiency; V154M; stimulator of interferon genes; type I interferon

Domaines: Sciences du Vivant [q-bio]

Delphine Bouis, Peggy Kirstetter, Florent Arbogast, Delphine Lamon, Virginia Delgado, et al.. Severe combined immunodeficiency in stimulator of interferon genes (STING) V154M/wild-type mice. Journal of Allergy and Clinical Immunology, 2019, 143 (2), pp.712-725.e5. ⟨10.1016/j.jaci.2018.04.034⟩. ⟨hal-03375897⟩