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

Abstract

The significance ofgene in tissue inflammation and cancer immunotherapy has been increasingly recognized. Intriguingly, common humanalleles R71H-G230A-R293Q () and G230A-R293Q () are carried by ~60% of East Asians and ~40% of Africans, respectively. Here, we examine the modulatory effects ofalleles on STING-associated vasculopathy with onset in infancy (SAVI), an autosomal dominant, fatal inflammatory disease caused by gain-of-function humanmutations. CD4 T cellpenia is evident in SAVI patients and mouse models. Usingknock-in mice expressing common humanalleles,, and, we found that, andsplenocytes resist STING1-mediated cell death ex vivo, establishing a critical role of STING1 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, themice 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 dominantalleles. STING1 research and STING1-targeting immunotherapy should considerheterogeneity in humans.