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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:144

Article

Luksch, Hella¹  Stinson, W. Alexander⁴  Platt, Derek J.⁵  Qian, Wei³  Kalugotla, Gowri³  Miner, Cathrine A.³  Bennion, Brock G.⁴  Gerbaulet, Alexander²  Roesen-Wolff, Angela¹  Miner, Jonathan J.^3,4,5 

[1] Univ Hosp Carl Gustav Carus, Dept Pediat, Dresden, Germany

[2] Tech Univ Dresden, Inst Immunol, Dresden, Germany

[3] Washington Univ, Sch Med, Dept Med, 660 South Euclid Ave,Box 8045, St Louis, MO 63110 USA

[4] Washington Univ, Sch Med, Dept Pathol & Immunol, 660 South Euclid Ave,Box 8045, St Louis, MO 63110 USA

[5] Washington Univ, Sch Med, Dept Mol Microbiol, 660 South Euclid Ave,Box 8045, St Louis, MO 63110 USA

关键词: Stimulator of interferon genes;    vasculopathy;    interferonopathy;    innate immunity;    STING-associated vasculopathy with onset in infancy;    cyclic GMP-AMP synthase;   

DOI  :  10.1016/j.jaci.2019.01.044

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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