{"doi":"10.7554/elife.96790.2.sa1","title":"Reviewer #2 (Public Review): The common TMEM173 HAQ, AQ alleles rescue CD4 T cellpenia, restore T-regs, and prevent SAVI (N153S) inflammatory disease in mice","abstract":"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.Common human HAQ, AQ TMEM173 alleles dominate the gain-of-function SAVI(N154S) TMEM173 mutant in mice.","journal":null,"year":2024,"id":502318,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9577,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1193673,"name":"Lennon A Saldarriaga","orcid":null,"position":1,"is_corresponding":false},{"id":1352245,"name":"Ann T Pham","orcid":null,"position":2,"is_corresponding":false},{"id":1352246,"name":"Amir M Emtiazjoo","orcid":null,"position":3,"is_corresponding":false},{"id":1352247,"name":"Ashish K Sharma","orcid":null,"position":4,"is_corresponding":false},{"id":1352248,"name":"Andrew J Bryant","orcid":null,"position":5,"is_corresponding":false},{"id":660598,"name":"Lei Jin","orcid":"0009-0007-2075-8723","position":6,"is_corresponding":false},{"id":1193313,"name":"Alexandra Aybar-Torres","orcid":"0000-0002-6500-2707","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-19T02:10:23.709105Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}