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

Hella Luksch, W. Alexander Stinson, Derek J. Platt, Wei Qian, Gowri Kalugotla, Cathrine A. Miner, Brock G. Bennion, Alexander Gerbaulet, Angela Rösen-Wolff, Jonathan J. Miner

Research output: Contribution to journalArticlepeer-review

36 Scopus citations


Background: 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. Objective: 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. Methods: 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. Results: 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)254-266.e8
JournalJournal of Allergy and Clinical Immunology
Issue number1
StatePublished - Jul 2019


  • STING-associated vasculopathy with onset in infancy
  • Stimulator of interferon genes
  • cyclic GMP-AMP synthase
  • innate immunity
  • interferonopathy
  • vasculopathy


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