Radioresistant Cells in STING Gain-of-function Mice Initiate Lymphocyte-dependent Lung Inflammation and IFN?-dependent Mortality

Pediatric patients with constitutively active mutations in the cytosolic dsDNA sensing adaptor STING develop an autoinflammatory syndrome known as STING Associated Vasculopathy with onset in Infancy (SAVI). SAVI patients have elevated interferon stimulated gene expression and suffer from interstitial lung disease (ILD) with lymphocyte predominate bronchus associated lymphoid tissue (BALT). Mice harboring SAVI mutations (STING V154M or VM) that recapitulate human disease also develop lymphocyte rich BALT formation. Ablation of either T or B lymphocytes prolongs survival of SAVI mice, but lung immune aggregates persist, indicating that T cells and B cells can independently be recruited as BALT. VM T cells produced IFN? and IFN?R deficiency prolonged the survival of SAVI mice; however, T cell dependent recruitment of infiltrating myeloid cells to the lung was independent of IFN?. Lethally irradiated VM recipients fully reconstituted with WT BM-derived cells still developed ILD, pointing to a critical role for VM-expressing radioresistant parenchymal and/or stromal cells in the recruitment and activation of pathogenic lymphocytes. We identified lung endothelial cells as radioresistant cells which express STING. Transcriptional analysis of VM endothelial cells revealed upregulation of chemokines, pro-inflammatory cytokines, and genes associated with antigen presentation. Together, our data show that VM-expressing radioresistant cells play a key role in the initiation of lung disease in VM mice and provide new insights for the treatment of SAVI patients, with implications for ILD associated with other connective tissue disorders. Overall design: 4 samples from individual WT B6 mouse controls, and 5 samples from individual STING V154M B6 litter mates.