STING-associated lung disease in mice relies on T cells but not type I interferon

• Published in: Journal of allergy and clinical immunology Vol. 144; no. 1; pp. 254 - 266.e8
• Main Authors: Luksch, Hella, Stinson, W. Alexander, Platt, Derek J., Qian, Wei, Kalugotla, Gowri, Miner, Cathrine A., Bennion, Brock G., Gerbaulet, Alexander, Rösen-Wolff, Angela, Miner, Jonathan J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2019; Elsevier Limited
• Subjects: Adaptive immunity; AMP; Animals; Apoptosis; B-Lymphocytes - immunology; Bone marrow; Bone Marrow Transplantation; Cell growth; Cyclic GMP; cyclic GMP-AMP synthase; Effector cells; Experiments; Female; Gain of Function Mutation; Gene expression; Immunoregulation; innate immunity; Interferon regulatory factor 3; Interferon regulatory factor 7; Interferon Type I - immunology; interferonopathy; Laboratory animals; Lung - immunology; Lung diseases; Lung Diseases - immunology; Lymphocytes; Lymphocytes B; Lymphocytes T; Male; Membrane Proteins - genetics; Membrane Proteins - immunology; Mice, Transgenic; Mutation; Nucleotidyltransferases - immunology; Pathogenesis; RAG gene; RAG1 protein; Recombination; Spleen - immunology; Stimulator of interferon genes; STING-associated vasculopathy with onset in infancy; T cell receptors; T-Lymphocytes - immunology; vasculopathy; α-Interferon; β-Interferon; Germany; SAVI; BMT; Stimulator of interferon genes; NF-κB; innate immunity; JAK; MIP; Sca-1; cyclic GMP-AMP synthase; interferonopathy; cGAS; Tcrb; STING; vasculopathy; STING-associated vasculopathy with onset in infancy; IRF; ISG; Rag2; WT; HSPC; IFNAR1; Rag1
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2019.01.044

Monogenic interferonopathies are thought to be mediated by type I interferon. For example, a gain-of-function mutation in stimulator of interferon genes (STING; N153S) upregulates type I interferon–stimulated genes and causes perivascular inflammatory lung disease in mice. The equivalent mutation in human subjects also causes lung disease, which is thought to require signaling through the cyclic GMP-AMP synthase (cGAS)–STING pathway and subsequent activation of interferon regulatory factors (IRFs) 3 and 7, type I interferon, and interferon-stimulated genes. We set out to define the roles of cGAS, IRF3, IRF7, the type I interferon receptor (IFN-α and IFN-β receptor subunit 1 [IFNAR1]), T cells, and B cells in spontaneous lung disease in STING N153S mice. STING N153S mice were crossed to animals lacking cGAS, IRF3/IRF7, IFNAR1, adaptive immunity, αβ T cells, and mature B cells. Mice were evaluated for spontaneous lung disease. Additionally, bone marrow chimeric mice were assessed for lung disease severity and survival. Lung disease in STING N153S mice developed independently of cGAS, IRF3/IRF7, and IFNAR1. Bone marrow transplantation revealed that certain features of STING N153S–associated disease are intrinsic to the hematopoietic compartment. Recombination-activating gene 1 (Rag1)−/− STING N153S mice that lack adaptive immunity had no lung disease, and T-cell receptor β chain (Tcrb)−/− STING N153S animals only had mild disease. STING N153S led to a reduction in percentages and numbers of naive and regulatory T cells, as well as an increased frequency of cytokine-producing effector T cells. Spontaneous lung disease in STING N153S mice develops independently of type I interferon signaling and cGAS. STING N153S relies primarily on T cells to promote lung disease in mice. [Display omitted]