{"doi":"10.1126/scitranslmed.adg6822","title":"Identification of unstable regulatory and autoreactive effector T cells that are expanded in patients with <i>FOXP3</i> mutations","abstract":"Studies of the monogenic autoimmune disease immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) have elucidated the essential function of the transcription factor FOXP3 and thymic-derived regulatory T cells (T regs ) in controlling peripheral tolerance. However, the presence and the source of autoreactive T cells in IPEX remain undetermined. Here, we investigated how FOXP3 deficiency affects the T cell receptor (TCR) repertoire and T reg stability in vivo and compared T cell abnormalities in patients with IPEX with those in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED). To study T regs independently of their phenotype and to analyze T cell autoreactivity, we combined T reg -specific demethylation region analyses, single-cell multiomic profiling, and bulk TCR sequencing. We found that patients with IPEX, unlike patients with APECED, have expanded autoreactive T cells originating from both autoreactive effector T cells (T effs ) and T regs . In addition, a fraction of the expanded T regs from patients with IPEX lost their phenotypic and functional markers, including CD25 and FOXP3. Functional experiments with CRISPR-Cas9–mediated FOXP3 knockout T regs and T regs from patients with IPEX indicated that the patients’ T regs gain a T H 2-skewed T eff -like function, which is consistent with immune dysregulation observed in these patients. Analyses of FOXP3 mutation-carrier mothers and a patient with IPEX after hematopoietic stem cell transplantation indicated that T regs expressing nonmutated FOXP3 prevent the accumulation of autoreactive T effs and unstable T regs . These findings could be directly used for diagnostic and prognostic purposes and for monitoring the effects of immunomodulatory treatments.","journal":"Science Translational Medicine","year":2023,"id":332984,"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":24,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9488,"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":711557,"name":"Esmond Lee","orcid":"0000-0001-5073-7922","position":1,"is_corresponding":false},{"id":993697,"name":"Jason Nideffer","orcid":"0000-0002-4421-8656","position":2,"is_corresponding":false},{"id":428658,"name":"Akshaya Ramachandran","orcid":"0000-0002-8727-2046","position":3,"is_corresponding":false},{"id":1059733,"name":"Bing Wang","orcid":"0000-0001-5106-6681","position":4,"is_corresponding":false},{"id":459015,"name":"Jeanette Baker","orcid":"0000-0002-0753-0317","position":5,"is_corresponding":false},{"id":501557,"name":"Melissa Mavers","orcid":"0000-0001-5452-9530","position":6,"is_corresponding":false},{"id":274197,"name":"Uma Lakshmanan","orcid":"0009-0006-5121-2558","position":7,"is_corresponding":false},{"id":274202,"name":"Mansi Narula","orcid":"0000-0002-5148-7256","position":8,"is_corresponding":false},{"id":1060205,"name":"Amy Kang-hee Garrett","orcid":null,"position":9,"is_corresponding":false},{"id":1059734,"name":"Janika Schulze","orcid":"0000-0003-0433-2005","position":10,"is_corresponding":false},{"id":1059735,"name":"Sven Olek","orcid":"0000-0003-3196-7436","position":11,"is_corresponding":false},{"id":1059736,"name":"Louis Marois","orcid":"0000-0002-1567-5583","position":12,"is_corresponding":false},{"id":1059737,"name":"Yaël Gernez","orcid":"0000-0001-6453-2901","position":13,"is_corresponding":false},{"id":295460,"name":"Monica Bhatia","orcid":"0009-0002-9110-4632","position":14,"is_corresponding":false},{"id":263452,"name":"Hey Chong","orcid":"0000-0002-6938-9267","position":15,"is_corresponding":false},{"id":295464,"name":"Jolán E. Walter","orcid":"0000-0002-6192-0703","position":16,"is_corresponding":false},{"id":280626,"name":"Maleewan Kitcharoensakkul","orcid":"0000-0002-1080-4681","position":17,"is_corresponding":false},{"id":971343,"name":"Abigail Lang","orcid":"0000-0002-0186-691X","position":18,"is_corresponding":false},{"id":241308,"name":"Megan A. Cooper","orcid":"0000-0002-5696-172X","position":19,"is_corresponding":false},{"id":274205,"name":"Alice Bertaina","orcid":"0000-0002-3729-436X","position":20,"is_corresponding":false},{"id":356717,"name":"Maria Grazia Roncarolo","orcid":"0000-0003-1636-1495","position":21,"is_corresponding":false},{"id":395328,"name":"Eric Meffre","orcid":"0000-0003-4326-0171","position":22,"is_corresponding":false},{"id":237029,"name":"Rosa Bacchetta","orcid":"0000-0002-0606-6268","position":23,"is_corresponding":false},{"id":1059732,"name":"Šimon Borna","orcid":"0000-0001-8445-2634","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":null,"created_at":"2026-07-19T01:09:35.125543Z","pmid":"38117899","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":[]}