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

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) m..., Please see the \"Method\" section of the manuscript., , # Data from: The common TMEM173 HAQ, AQ alleles rescue CD4 T cellpenia, restore T-regs, and prevent SAVI (N153S) inflammatory disease in mice

[https://doi.org/10.5061/dryad.m0cfxppcv](https://doi.org/10.5061/dryad.m0cfxppcv)

## Description of the data and file structure

**Figure 1. Splenocytes from *HAQ, AQ*, and *Q293* mice are resistant to STING-mediated cell death *ex vivo*. (A).** C57BL/6N splenocytes were treated directly (no transfection) with diABZI (100ng/ml), RpRpss-Cyclic di-AMP (5 μg/ml) or 2′3′-cGAMP (10μg/ml), DMXAA (25μg/ml) for 24hrs in culture. CD4, CD8 T cells and CD19 B cells death were determined by PI staining. (**B)**. Splenocytes from C57BL/6N mice were pre-treated with indicated small molecules, GSK2334470 (1.25µM), GSK8612 (2.5µM), Bx-795 (0.5µM), QVD-OPH (25µM) for 2hrs.  diABZI (100ng/ml) was added in culture for another 24hrs. Dead cells were determined by PI staining. (**C-D).** Flowcytometry of *HAQ*, *AQ*, IFNAR1-/- or C57BL/6N splenocytes treated with d...

由TMEM173基因编码的STING在组织炎症及癌症免疫治疗中的重要性日益受到认可。有趣的是，东亚人群中约60%携带常见人类STING等位基因R71H-G230A-R293Q（HAQ），非洲人群中约40%携带G230A-R293Q（AQ）。本研究探讨HAQ、AQ等位基因对婴儿期起病的STING相关血管病变（SAVI，一种由人类STING功能获得性突变导致的常染色体显性致命性炎症疾病）的调控作用。CD4 T细胞减少症在SAVI患者及小鼠模型中均有体现。通过使用表达常见人类STING等位基因HAQ、AQ及Q293的STING基因敲入小鼠，我们发现HAQ、AQ及Q293脾细胞可在体外抵抗STING介导的细胞死亡，表明STING的293位残基在细胞死亡中发挥关键作用。HAQ/SAVI(N153S)和AQ/SAVI(N153S)小鼠未出现CD4 T细胞减少症。HAQ/SAVI(N153S)、AQ/SAVI(N153S)小鼠的调节性T细胞数量分别约为WT/SAVI(N153S)小鼠的10倍和20倍……详见手稿的“方法”部分。

# 数据来源：常见TMEM173 HAQ、AQ等位基因可挽救CD4 T细胞减少症、恢复调节性T细胞并预防SAVI(N153S)炎症疾病（小鼠实验）
[https://doi.org/10.5061/dryad.m0cfxppcv]

## 数据及文件结构描述

**图1. HAQ、AQ及Q293小鼠脾细胞在体外抵抗STING介导的细胞死亡**
(A) 将C57BL/6N小鼠脾细胞直接（未转染）用diABZI（100ng/ml）、RpRpss-环二AMP（5μg/ml）、2'3'-cGAMP（10μg/ml）或DMXAA（25μg/ml）处理24小时，通过PI染色检测CD4、CD8 T细胞及CD19 B细胞的死亡情况。
(B) 将C57BL/6N小鼠脾细胞用指定小分子药物（GSK2334470 1.25μM、GSK8612 2.5μM、Bx-795 0.5μM、QVD-OPH 25μM）预处理2小时，再加入diABZI（100ng/ml）继续培养24小时，通过PI染色检测死亡细胞。
(C-D) 对经d……处理的HAQ、AQ、IFNAR1-/-或C57BL/6N小鼠脾细胞进行流式细胞术分析……