
The common human TMEM173 alleles HAQ and AQ prevent STING-mediated CD4 T cell death, restore T-regulatory cells, and alleviate the inflammatory SAVI disease in mice.


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The significance of STING (encoded by the TMEM173 gene), in tissue inflammation and cancer immunotherapy has been increasingly recognized. Intriguingly, common human STING alleles 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 of HAQ, AQ alleles on STING-associated vasculopathy with onset in infancy (SAVI), an autosomal dominant, fatal inflammatory disease caused by gain-of-function human STING mutations. CD4 T cellpenia is evident in SAVI patients and mouse models. Using STING knock-in mice expressing common human STING alleles HAQ , AQ , and Q293 , we found that HAQ, AQ , and Q293 splenocytes resist STING-mediated cell death ex vivo, establishing a critical role of STING residue 293 in cell death. The HAQ/SAVI(N153S) and AQ/SAVI(N153S) mice did not have CD4 T cellpenia. The HAQ/SAVI(N153S), AQ/SAVI(N153S) mice have more (∼10-fold, ∼20-fold, respectively) T-regs than WT/SAVI(N153S) mice. Remarkably, while they have comparable TBK1, IRF3, and NFκB activation as the WT/SAVI , the AQ/SAVI mice have no tissue inflammation, regular body weight, and normal lifespan. 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.

Teaser: One copy of the common human HAQ or AQ TMEM173 gene prevents the gain-of-function TMEM173 mutant-caused SAVI disease in mice.

### Competing Interest Statement

The authors have declared no competing interest.

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

common-tmem173-haq-and-aq-alleles-prevent-cd4-t-cell-death-restore-t-regs-and-alleviate-savi-n153s-inflammatory-disease-in-mice


Common TMEM173 HAQ and AQ Alleles Prevent CD4 T Cell Death, Restore T-Regs, and Alleviate SAVI (N153S) Inflammatory Disease in Mice
