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

J Allergy Clin Immunol. 2019 Feb;143(2):712-725.e5. doi: 10.1016/j.jaci.2018.04.034. Epub 2018 May 23.


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.

Keywords: Severe combined immunodeficiency; V154M; stimulator of interferon genes; type I interferon.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agammaglobulinemia
  • Animals
  • B-Lymphocytes / physiology*
  • Cell Differentiation / genetics
  • Disease Models, Animal
  • Humans
  • Inflammation / genetics*
  • Interferon Type I / metabolism
  • Killer Cells, Natural / immunology*
  • Membrane Proteins / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation / genetics*
  • Receptor, Interferon alpha-beta / genetics
  • Severe Combined Immunodeficiency / genetics*
  • T-Lymphocytes / physiology*


  • Ifnar1 protein, mouse
  • Interferon Type I
  • Membrane Proteins
  • Sting1 protein, mouse
  • Receptor, Interferon alpha-beta