Radioresistant cells in STING gain-of-function mice initiate lymphocyte dependent lung inflammation and IFNγ dependent mortality

Abstract

Abstract Pediatric patients with gain-of-function (GOF) mutations in the cytosolic dsDNA sensing adaptor STING develop an autoinflammatory syndrome known as STING Associated Vasculopathy with onset in Infancy (SAVI). SAVI patients show elevated interferon signature genes and suffer from interstitial lung disease (ILD) with lymphocyte predominate bronchus associated lymphoid tissue (BALT). We genetically engineered SAVI mice (STING V154M or VM) that recapitulates human disease, including lymphocyte rich ILD, and found by genetic ablation that lymphocytes are required for lung pathology. However, while ablation of either T or B lymphocytes prolongs survival, lung immune aggregates persist, indicating either can independently be recruited as BALT. Using radiation chimeras, we found that hematopoietic stem cell (HSC) derived STING GOF was neither sufficient nor required for VM lung disease, suggesting a role for lung radioresistant parenchymal and stromal cell STING GOF in SAVI. We identified lung endothelia as putative radioresistant cells which express STING and confirmed expression by IF microscopy and FACS. FACS analysis also revealed SAVI lung endothelia upregulate MHCII, but only when sufficient for IFNgR. VM T cells produce IFNg, and IFNgR deficiency was sufficient to prevent endothelial MHCII upregulation and attenuate mortality. However, HSC STING GOF was not required for endothelial MHCII upregulation, suggesting stromal intrinsic STING GOF initiates this outcome. These findings suggest that activation of STING in stromal and parenchymal cells play a key role the initiation of lung inflammation in patients with connective tissue disease ILD. Supported by: T32 GM107000 (MSTP); T32 AI132152 (KMG); F30 HL154674 (KMG); AI128358 (AMR/KAF); Lupus Research Alliance