Σφακιανάκης Αλέξανδρος
ΩτοΡινοΛαρυγγολόγος
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Πέμπτη 14 Φεβρουαρίου 2019

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

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

Graphical abstract for this article



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