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

Abstract

STING activation induces lymphocyte cell death that is independent of type I IFNs. Thein vivosignificance and mechanism of STING-mediated cell death is unclear. Using STING knock-in mice, we found that lymphocytes from theHAQ,AQ, andQ293mice are resistant to STING-mediated cell deathex vivo, establishing a critical role of STING residue 293 in cell death. CD4 T cellpenia is evident in STING-associated vasculopathy with onset in infancy (SAVI), an autosomal dominant, fatal inflammatory disease caused by gain-of-function human STING mutations. TheHAQ/SAVI(N153S)andAQ/SAVI(N153S)mice have similar spleen CD4 T cells as theWTmice reversing the CD4 T cellpenia by the gain-of-function N153S STING. TheHAQ/SAVI(N153S), AQ/SAVI(N153S)mice have more (∼10-fold, ∼20-fold, respectively) T-regs thanWT/SAVI(N153S)mice. Remarkably, while have comparable TBK1, IRF3, NFκB activation as theWT/SAVI, theAQ/SAVImice have no tissue inflammation, regular body weight, and normal lifespan. The type I IFNs-independent function of STING in health and diseases has been increasingly recognized. 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.One-sentence summaryThe CommonTMEM173allelesHAQ, AQprevent SAVI disease.