The common TMEM173 HAQ, AQ alleles rescue CD4 T cell death, restore T-regs, and prevent SAVI (N153S) inflammatory disease in mice

STING activation induces lymphocyte cell death that is independent of type I IFNs. The in vivo significance and mechanism of STING-mediated cell death is unclear. Using STING knock-in mice, we found that lymphocytes from the HAQ, AQ, and Q293 mice are resistant to STING-mediated cell death ex vivo, establishing a critical role of STING residue 293 in cell death. CD4 T cellpenia is evident in STING-associated vasculopathy with onset in infancy (SAVI), an autosomal dominant, fatal inflammatory disease caused by gain-of-function human STING mutations. The HAQ/SAVI(N153S) and AQ/SAVI(N153S) mice have similar spleen CD4 T cells as the WT mice reversing the CD4 T cellpenia by the gain-of-function N153S STING. The HAQ/SAVI(N153S), AQ/SAVI(N153S) mice have more (~10-fold, ~20-fold, respectively) T-regs than WT/SAVI(N153S) mice. Remarkably, while have comparable TBK1, IRF3, NFκB activation as the WT/SAVI, the AQ/SAVI mice have no tissue inflammation, regular body weight, and normal lifespan. The type I IFNs-independent function of STING in health and diseases has been increasingly recognized. We propose that STING activation promotes tissue inflammation by depleting T-regs cells in vivo. Billions of modern humans have the dominant HAQ, AQ alleles. STING research and STING targeting immunotherapy should consider TMEM173 heterogeneity in humans.