Publication date: Available online 14 February 2019
Source: Journal of Allergy and Clinical Immunology
Author(s): 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
Abstract
Background
Monogenic interferonopathies are thought to be mediated by type I interferon (IFN). For example, a gain-of-function mutation in STING (STING N153S) up-regulates type I IFN-stimulated genes (ISGs) and causes perivascular inflammatory lung disease in mice. The equivalent mutation in humans also causes lung disease, which is thought to require signaling through the cGAS-STING pathway and subsequent activation of IFN regulatory factors (IRF) 3/7, type I IFN, and ISGs.
Objective
We set out to define the roles of cGAS, IRF3, IRF7, the type I IFN receptor (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. Rag1-/- STING N153S mice that lack adaptive immunity had no lung disease, and Tcrβ-/- STING N153S animals only developed mild disease. STING N153S led to a reduction in percent and number 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 IFN signaling and cGAS. STING N153S relies primarily on T cells to promote lung disease in mice.
Graphical abstract
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