Gain-of-function STING mutations induce T cell death in the SAVI mouse

Abstract

Abstract STING is ER-localized protein that plays a central role in the innate immune response to microbial DNA, cyclic di-nucleotide and aberrant host DNA. We previously established a STING-associated vasculopathy with onset in infancy (SAVI) mouse model by introducing the N153S mutation in the mouse STING (N154S in the human STING). The SAVI mouse recapitulates several abnormal phenotypes observed in human patients, including inflammatory lung disease, T cell cytopenia and premature death; and these disease phenotypes surprisingly occur independent of IRF3. To further investigate the SAVI disease mechanism, we focused on the role of STING in T cell survival. We found that both mature CD4 and CD8 T cells in STING N153S mice are undergoing apoptosis. Inducible expression of STING N154S but not WT STING in Jurkat T cells also caused robust apoptotic cell death. Mechanistically, we defined a novel structural motif in the STING protein as well as an IFN-independent signaling cascade that are required for STING gain-of-function mutants to drive T cell death. We hope that genetic or pharmacological targeting of the STING-mediated cell death signaling pathway would be therapeutically useful for treating SAVI patients.