{"doi":"10.1161/atvbaha.123.319674","title":"Oxidized Phospholipid oxPAPC Alters Regulatory T-Cell Differentiation and Decreases Their Protective Function in Atherosclerosis in Mice","abstract":"BACKGROUND: Regulatory T cells (T regs ) are protective in atherosclerosis but reduced during disease progression due to cell death and loss of stability. However, the mechanisms of T reg dysfunction remain unknown. Oxidized phospholipids are abundant in atherosclerosis and can activate innate immune cells, but little is known regarding their impact on T cells. Given T reg loss during atherosclerosis progression and oxidized phospholipid levels in the plaque microenvironment, we investigated whether oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (oxPAPC), an oxidized phospholipid associated with atherosclerotic plaques, alters T reg differentiation and function. METHODS: CD4 + T cells were polarized to T reg , T helper (Th) 1, and Th17 cells with or without oxPAPC and assessed by flow cytometry. Gene expression in oxPAPC-treated T regs was analyzed by bulk RNA sequencing. Functional studies of oxPAPC-induced T regs were performed by coculturing T regs with CellTrace Violet–labeled cells in vitro, and by adoptively transferring T regs to hyperlipidemic Ldlr −/− mice to measure atherosclerosis progression. RESULTS: Compared with controls, oxPAPC-treated T regs were less viable, but surviving cells expressed higher levels of the Th1-associated markers T-bet, CXCR3, and IFN (interferon)-γ. Th1 and Th17 skewing cultures were unaltered by oxPAPC. IFN-γ is linked to T reg instability, thus T reg polarization experiments were repeated using Ifngr1 −/− CD4 + T cells. IFNγR1 (INF gamma receptor 1) deficiency did not improve cell viability in oxPAPC-treated T regs ; however, T-bet and IFN-γ expression was not increased in surviving cells suggesting a role for IFN-γsignaling. OxPAPC-treated T regs were less suppressive in vitro, and adoptive transfer studies in hyperlipidemic Ldlr −/− mice showed that oxPAPC-induced T regs possessed altered tissue homing and were insufficient to inhibit atherosclerosis progression. CONCLUSIONS: OxPAPC elicits T reg -specific changes altering T reg differentiation and inducing a Th1-like phenotype in surviving cells partially through IFN-γ signaling. This is biologically relevant as oxPAPC-treated T regs do not reduce atherosclerosis progression in Ldlr −/− mice. This study supports the role of oxidized phospholipids in negatively impacting T reg differentiation and atheroprotective function.","journal":"Arteriosclerosis Thrombosis and Vascular Biology","year":2023,"id":341598,"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":15,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9538,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1077552,"name":"Sydney A. Palmer","orcid":"0009-0001-7585-1067","position":1,"is_corresponding":false},{"id":1077553,"name":"Harrison P. Smith","orcid":"0009-0004-7725-6810","position":2,"is_corresponding":false},{"id":1077554,"name":"Lilly E. Stephens","orcid":"0009-0000-3749-9739","position":3,"is_corresponding":false},{"id":1019816,"name":"Amy S. Major","orcid":"0000-0003-0377-2041","position":4,"is_corresponding":false},{"id":1077551,"name":"Brenna D. Appleton","orcid":"0000-0001-7939-4783","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T01:11:08.077724Z","pmid":"37675632","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":[]}