The common alleles rescue CD4 T cellpenia, restore T-regs, and prevent inflammatory disease in mice.

The significance of STING (encoded by the gene) in tissue inflammation and cancer immunotherapy has been increasingly recognized. Intriguingly, common human alleles R71H-G230A-R293Q ( and G230A-R293Q () are carried by 60% of East Asians and ~40% of Africans, respectively. Here, we examine the modulatory effects of alleles on STING-associated vasculopathy with onset in infancy (SAVI), an autosomal dominant, fatal inflammatory disease caused by gain-of-function human mutations. CD4 T cellpenia is evident in SAVI patients and mouse models. Using STING knock-in mice expressing common human alleles , , and , we found that , and splenocytes resist STING-mediated cell death establishing a critical role of STING residue 293 in cell death. The and mice did not have CD4 T cellpenia. The mice have more (10-fold, ~20-fold, respectively) T-regs than mice. Remarkably, while they have comparable TBK1, IRF3, and NFκB activation as the , the mice have no tissue inflammation, regular body weight, and normal lifespan. We propose that STING activation promotes tissue inflammation by depleting T-regs cells . Billions of modern humans have the dominant alleles. STING research and STING-targeting immunotherapy should consider heterogeneity in humans.