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

• Published in: Journal of allergy and clinical immunology Vol. 143; no. 2; pp. 712 - 725.e5
• Main Authors: Bouis, Delphine, Kirstetter, Peggy, Arbogast, Florent, Lamon, Delphine, Delgado, Virginia, Jung, Sophie, Ebel, Claudine, Jacobs, Hugues, Knapp, Anne-Marie, Jeremiah, Nadia, Belot, Alexandre, Martin, Thierry, Crow, Yanick J., André-Schmutz, Isabelle, Korganow, Anne-Sophie, Rieux-Laucat, Frédéric, Soulas-Sprauel, Pauline
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2019; Elsevier
• Subjects: Agammaglobulinemia; Animals; B-Lymphocytes - physiology; Cell Differentiation - genetics; Disease Models, Animal; Humans; Inflammation - genetics; Interferon Type I - metabolism; Killer Cells, Natural - immunology; Life Sciences; Membrane Proteins - genetics; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation - genetics; Receptor, Interferon alpha-beta - genetics; Severe combined immunodeficiency; Severe Combined Immunodeficiency - genetics; stimulator of interferon genes; T-Lymphocytes - physiology; type I interferon; V154M; DD; V154M; ILC; LN; Severe combined immunodeficiency; CLP; LT; DN; BM; SCID; FITC; TBK1; HSC; ISG; WT; GOF; KO; IFNAR; SAVI; Treg; ER; type I interferon; APC; cGAMP; PE; stimulator of interferon genes; STING; NK; BrdU
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2018.04.034

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. 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. 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. 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. 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.