IFNγ Contributes to Splenic B and T cell Activation and Cytopenia in STING Gain-of-Function Autoinflammation

Abstract

Abstract cGAS-STING is a cytosolic dsDNA sensing pathway whose regulation is vital to immune homeostasis. Constitutively active STING mutations cause an autoinflammatory syndrome known as STING Associated Vasculopathy with onset in Infancy (SAVI). Pediatric SAVI patients develop treatment resistant lung fibrosis associated with immune abnormalities, including lymphopenia with hyperactivity of remaining lymphocytes and an interferon-stimulated gene signature. Unlike other cGAS-STING driven autoinflammatory syndromes in which Type 1 interferons (T1IFNs) mediate pathology, loss of the T1IFN receptor fails to prevent disease in mice expressing the STINGV154M SAVI (VM) mutation. Instead, lymphocytes play a critical role in SAVI, as VM Rag1−/− mice fail to develop lung disease. Thus, we sought to test whether T cell production of IFNγ (Type 2 IFN) could be a causal mechanism of disease in SAVI, and predicted that IFNγR1 and TCRβ deficiency ought to rescue SAVI disease in a similar fashion. In alignment with our expectations, we found that B cell lymphopenia and hyperactivity were equally rescued in VM IFNγR1−/− and VM TCRβ−/− mice. Moreover, IFNγR1 deficiency also led to improvements in thymic development, T lymphopenia, and hyperactivity. However, despite resolution of splenic lymphocyte defects in VM IFNγR1−/− and VM TCRβ−/− mice, these mice continued to develop fibrotic lung disease. This finding indicates a T cell and IFNγ independent process in SAVI lung disease pathogenesis. In concordance with this, we have recently found that B cells accumulate in the VM lung with a highly activated phenotype independent of αβ T cells, suggesting a potential role for B cells in the etiology of SAVI fibrotic lung disease which we are actively investigating.