{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T21:23:58Z","timestamp":1793913838005,"version":"4.8.0"},"reference-count":61,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"727","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2023,12,20]]},"abstract":"<jats:p>\n                    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\n                    <jats:sub>regs<\/jats:sub>\n                    ) 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\n                    <jats:sub>reg<\/jats:sub>\n                    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\n                    <jats:sub>regs<\/jats:sub>\n                    independently of their phenotype and to analyze T cell autoreactivity, we combined T\n                    <jats:sub>reg<\/jats:sub>\n                    -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\n                    <jats:sub>effs<\/jats:sub>\n                    ) and T\n                    <jats:sub>regs<\/jats:sub>\n                    . In addition, a fraction of the expanded T\n                    <jats:sub>regs<\/jats:sub>\n                    from patients with IPEX lost their phenotypic and functional markers, including CD25 and FOXP3. Functional experiments with CRISPR-Cas9\u2013mediated FOXP3 knockout T\n                    <jats:sub>regs<\/jats:sub>\n                    and T\n                    <jats:sub>regs<\/jats:sub>\n                    from patients with IPEX indicated that the patients\u2019 T\n                    <jats:sub>regs<\/jats:sub>\n                    gain a T\n                    <jats:sub>H<\/jats:sub>\n                    2-skewed T\n                    <jats:sub>eff<\/jats:sub>\n                    -like function, which is consistent with immune dysregulation observed in these patients. Analyses of\n                    <jats:italic>FOXP3<\/jats:italic>\n                    mutation-carrier mothers and a patient with IPEX after hematopoietic stem cell transplantation indicated that T\n                    <jats:sub>regs<\/jats:sub>\n                    expressing nonmutated\n                    <jats:italic>FOXP3<\/jats:italic>\n                    prevent the accumulation of autoreactive T\n                    <jats:sub>effs<\/jats:sub>\n                    and unstable T\n                    <jats:sub>regs<\/jats:sub>\n                    . These findings could be directly used for diagnostic and prognostic purposes and for monitoring the effects of immunomodulatory treatments.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adg6822","type":"journal-article","created":{"date-parts":[[2023,12,20]],"date-time":"2023-12-20T13:58:11Z","timestamp":1703080691000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":32,"title":["Identification of unstable regulatory and autoreactive effector T cells that are expanded in patients with\n                    <i>FOXP3<\/i>\n                    mutations"],"prefix":"10.1126","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8445-2634","authenticated-orcid":true,"given":"\u0160imon","family":"Borna","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esmond","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA."},{"name":"Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4421-8656","authenticated-orcid":true,"given":"Jason","family":"Nideffer","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akshaya","family":"Ramachandran","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5106-6681","authenticated-orcid":true,"given":"Bing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0753-0317","authenticated-orcid":true,"given":"Jeanette","family":"Baker","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA 94305, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5452-9530","authenticated-orcid":true,"given":"Melissa","family":"Mavers","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5121-2558","authenticated-orcid":true,"given":"Uma","family":"Lakshmanan","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5148-7256","authenticated-orcid":true,"given":"Mansi","family":"Narula","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy Kang-hee","family":"Garrett","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0433-2005","authenticated-orcid":true,"given":"Janika","family":"Schulze","sequence":"additional","affiliation":[{"name":"Epimune GmbH, Berlin 12489, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3196-7436","authenticated-orcid":true,"given":"Sven","family":"Olek","sequence":"additional","affiliation":[{"name":"Ivana Turbachova Laboratory for Epigenetics, Precision for Medicine GmbH, Berlin 12489, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1567-5583","authenticated-orcid":true,"given":"Louis","family":"Marois","sequence":"additional","affiliation":[{"name":"Department of Medicine, Immunology and Allergy Service, CHU de Qu\u00e9bec\u2013Laval University, Quebec G1V 4G2, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yael","family":"Gernez","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Allergy, Rheumatology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, 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St. Petersburg, FL 33701, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1080-4681","authenticated-orcid":true,"given":"Maleewan","family":"Kitcharoensakkul","sequence":"additional","affiliation":[{"name":"Divisions of Rheumatology\/Immunology and Allergy and Pulmonary Medicine, Department of Pediatrics, Washington University in St. Louis, St. Louis, MO 63110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0186-691X","authenticated-orcid":true,"given":"Abigail","family":"Lang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Allergy and Immunology, Ann and Robert H. Lurie Children\u2019s Hospital of Chicago, Chicago, IL 60611, USA."},{"name":"Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5696-172X","authenticated-orcid":true,"given":"Megan A.","family":"Cooper","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Rheumatology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3729-436X","authenticated-orcid":true,"given":"Alice","family":"Bertaina","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA."},{"name":"Center for Definitive and Curative Medicine (CDCM), Stanford University School of Medicine, Stanford, CA 94305, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1636-1495","authenticated-orcid":true,"given":"Maria Grazia","family":"Roncarolo","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA."},{"name":"Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA."},{"name":"Center for Definitive and Curative Medicine (CDCM), Stanford University School of Medicine, Stanford, CA 94305, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Meffre","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, 269 Campus Drive West, Stanford, CA 94305, 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