TY - JOUR
T1 - STING-associated lung disease in mice relies on T cells but not type I interferon
AU - Luksch, Hella
AU - Stinson, W. Alexander
AU - Platt, Derek J.
AU - Qian, Wei
AU - Kalugotla, Gowri
AU - Miner, Cathrine A.
AU - Bennion, Brock G.
AU - Gerbaulet, Alexander
AU - Rösen-Wolff, Angela
AU - Miner, Jonathan J.
N1 - Funding Information:
The Miner laboratory is supported by National Institutes of Health grant K08 AR070918 . The Rösen-Wolff laboratory is supported by the German Research Foundation (TRR237, B18).
Funding Information:
The Miner laboratory is supported by National Institutes of Health grant K08 AR070918. The R?sen-Wolff laboratory is supported by the German Research Foundation (TRR237, B18). The Miner laboratory is supported by National Institutes of Health grant K08 AR070918. The R?sen-Wolff laboratory is supported by the German Research Foundation (TRR237, B18). We thank the Washington University Pulmonary Morphology Core for assistance with tissue processing and staining. We thank L. Schulze, C. Haase, T. H?ring, and K. H?hne for technical assistance and advice. We also appreciate the following core facilities for their support: Genome Engineering Facility, Transgenic Core (both MPI-CBG Dresden), and BioDip. The Miner laboratory is supported by National Institutes of Health grant K08 AR070918. The R?sen-Wolff laboratory is supported by the German Research Foundation (TRR237, B18).
Publisher Copyright:
© 2019 American Academy of Allergy, Asthma & Immunology
PY - 2019/7
Y1 - 2019/7
N2 - 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.
AB - 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.
KW - STING-associated vasculopathy with onset in infancy
KW - Stimulator of interferon genes
KW - cyclic GMP-AMP synthase
KW - innate immunity
KW - interferonopathy
KW - vasculopathy
UR - http://www.scopus.com/inward/record.url?scp=85062632858&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2019.01.044
DO - 10.1016/j.jaci.2019.01.044
M3 - Article
C2 - 30772497
AN - SCOPUS:85062632858
VL - 144
SP - 254-266.e8
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
SN - 0091-6749
IS - 1
ER -