The commonTMEM173 HAQ, AQalleles rescue CD4 T cellpenia, restore T-regs, and preventSAVI (N153S)inflammatory disease in mice

The significance of STING (encoded by theTMEM173gene) in tissue inflammation and cancer immunotherapy has been increasingly recognized. Intriguingly, common humanTMEM173alleles R71H-G230A-R293Q (HAQ)and G230A-R293Q (AQ) are carried by ∼60% of East Asians and ∼40% of Africans, respectively. Here, we examine the modulatory effects ofHAQ, AQalleles on STING-associated vasculopathy with onset in infancy (SAVI), an autosomal dominant, fatal inflammatory disease caused by gain-of-function humanSTINGmutations. CD4 T cellpenia is evident in SAVI patients and mouse models. Using STING knock-in mice expressing common humanTMEM173allelesHAQ,AQ, andQ293, we found thatHAQ, AQ, andQ293splenocytes resist STING-mediated cell deathex vivo,establishing a critical role of STING residue 293 in cell death. TheHAQ/SAVI(N153S)andAQ/SAVI(N153S)mice did not have CD4 T cellpenia. TheHAQ/SAVI(N153S), AQ/SAVI(N153S)mice have more (∼10-fold, ∼20-fold, respectively) T-regs thanWT/SAVI(N153S)mice. Remarkably, while they have comparable TBK1, IRF3, and NFκB activation as theWT/SAVI, theAQ/SAVImice have no tissue inflammation, regular body weight, and normal lifespan. We propose that STING activation promotes tissue inflammation by depleting T-regs cellsin vivo. Billions of modern humans have the dominantHAQ, AQalleles. STING research and STING-targeting immunotherapy should considerTMEM173heterogeneity in humans.