دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: The common TMEM173 HAQ, AQ alleles rescue CD4 T cellpenia, restore T-regs, and prevent SAVI (N153S) inflammatory disease in mice.
المؤلفون: Aybar-Torres A; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL 32610, U.S.A., Saldarriaga LA; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL 32610, U.S.A., Pham AT; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL 32610, U.S.A., Emtiazjoo AM; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL 32610, U.S.A., Sharma AK; Division of Vascular Surgery & Endovascular Therapy, Department of Surgery, University of Florida, Gainesville, FL 32610, U.S.A., Bryant AJ; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL 32610, U.S.A., Jin L; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, FL 32610, U.S.A.
المصدر: BioRxiv : the preprint server for biology [bioRxiv] 2024 Jun 17. Date of Electronic Publication: 2024 Jun 17.
نوع المنشور: Journal Article; Preprint
اللغة: English
بيانات الدورية: Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet ISSN: 2692-8205 (Electronic) Linking ISSN: 26928205 NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE
مستخلص: The significance of STING (encoded by the TMEM173 gene) in tissue inflammation and cancer immunotherapy has been increasingly recognized. Intriguingly, common human TMEM173 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 TMEM173 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.
Competing Interests: Competing interests: Authors declare that they have no competing interests.
معلومات مُعتمدة: R01 HL152163 United States HL NHLBI NIH HHS
تواريخ الأحداث: Date Created: 20231027 Latest Revision: 20240701
رمز التحديث: 20240701
مُعرف محوري في PubMed: PMC10602033
DOI: 10.1101/2023.10.05.561109
PMID: 37886547
قاعدة البيانات: MEDLINE
الوصف
تدمد:2692-8205
DOI:10.1101/2023.10.05.561109