The common <i>Sting1 HAQ, AQ</i> alleles rescue CD4 T cellpenia, restore T-regs, and prevent <i>SAVI (N153S</i>) inflammatory disease in mice.

Abstract

The significance of <i>STING1</i> gene in tissue inflammation and cancer immunotherapy has been increasingly recognized. Intriguingly, common human <i>STING1</i> alleles R71H-G230A-R293Q (<i>HAQ</i>) and G230A-R293Q (<i>AQ</i>) are carried by ~60% of East Asians and ~40% of Africans, respectively. Here, we examine the modulatory effects of <i>HAQ, AQ</i> alleles on STING-associated vasculopathy with onset in infancy (SAVI), an autosomal dominant, fatal inflammatory disease caused by gain-of-function human <i>STING1</i> mutations. CD4 T cellpenia is evident in SAVI patients and mouse models. Using <i>Sting1</i> knock-in mice expressing common human <i>STING1</i> alleles <i>HAQ</i>, <i>AQ</i>, and <i>Q293</i>, we found that <i>HAQ, AQ</i>, and <i>Q293</i> splenocytes resist STING1-mediated cell death ex vivo, establishing a critical role of STING1 residue 293 in cell death. The <i>HAQ/SAVI(N153S</i>) and <i>AQ/SAVI(N153S</i>) mice did not have CD4 T cellpenia. The <i>HAQ/SAVI(N153S), AQ/SAVI(N153S</i>) mice have more (~10-fold, ~20-fold, respectively) T-regs than <i>WT/SAVI(N153S</i>) mice. Remarkably, while they have comparable TBK1, IRF3, and NFκB activation as the <i>WT/SAVI</i>, the <i>AQ/SAVI</i> mice have no tissue inflammation, regular body weight, and normal lifespan. We propose that STING1 activation promotes tissue inflammation by depleting T-regs cells in vivo. Billions of modern humans have the dominant <i>HAQ, AQ</i> alleles. STING1 research and STING1-targeting immunotherapy should consider <i>STING1</i> heterogeneity in humans.