Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 144, Issue 1, Pages 254-+Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2019.01.044
Keywords
Stimulator of interferon genes; vasculopathy; interferonopathy; innate immunity; STING-associated vasculopathy with onset in infancy; cyclic GMP-AMP synthase
Categories
Funding
- National Institutes of Health [K08 AR070918]
- German Research Foundation [TRR237]
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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; N1535) 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-alpha and IFN-beta 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, alpha beta 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 beta 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.
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