{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T08:20:39Z","timestamp":1787732439192,"version":"build-2784847793"},"reference-count":40,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T00:00:00Z","timestamp":1787702400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01 AI097134"],"award-info":[{"award-number":["R01 AI097134"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"abstract":"\n Objective<\/jats:title>\n \n Systemic lupus erythematosus (SLE) is characterized by type I interferon (IFN) signaling and adaptive immune dysregulation. We previously identified hypomethylation of\n HLA\u2010DRB1<\/jats:italic>\n and\n STAT1<\/jats:italic>\n in SLE CD8\n +<\/jats:sup>\n T cells, enabling aberrant IFN\u2010driven HLA\u2010DRB1 expression and expansion of a distinct CD8\n +<\/jats:sup>\n T cell subset. This study characterized CD8\n +<\/jats:sup>\n HLA\u2010DRB1\n +<\/jats:sup>\n T cells in lupus.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Peripheral blood CD8\n +<\/jats:sup>\n T cells from 11 patients with SLE and 12 healthy controls were analyzed by flow cytometry. Single\u2010cell RNA sequencing and T cell receptor sequencing, with and without IFN\u03b1 stimulation, in six patients with SLE and six matched healthy controls assessed transcriptional heterogeneity, exhaustion, senescence, and cytotoxicity.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n CD8\n +<\/jats:sup>\n HLA\u2010DRB1\n +<\/jats:sup>\n T cells were enriched within effector memory, CD45RA\n +<\/jats:sup>\n effector memory, and proliferative CD8\n +<\/jats:sup>\n T cells and were significantly expanded within the effector memory and proliferative compartment in SLE compared to healthy controls. These cells displayed paradoxical features of cytotoxicity, proliferation, exhaustion, and senescence. Compared to healthy controls, lupus CD8\n +<\/jats:sup>\n HLA\u2010DRB1\n +<\/jats:sup>\n T cells exhibited increased exhaustion, reduced cytotoxicity, and impaired antiviral pathways. IFN\u03b1 enhanced IFN\u03b3 responses in lupus CD8\n +<\/jats:sup>\n HLA\u2010DRB1\n +<\/jats:sup>\n T cells and exacerbated exhaustion and senescence. Despite up\u2010regulation of cytotoxic gene expression, IFN\u03b1 reduced CD107a surface mobilization, indicating impaired degranulation. Analysis of lupus nephritis data sets revealed that most kidney\u2010infiltrating CD8\n +<\/jats:sup>\n T cells are HLA\u2010DRB1\n +<\/jats:sup>\n . HLA\u2010DRB1 expression on peripheral CD8\n +<\/jats:sup>\n T cells from patients with SLE positively correlated with Systemic Lupus Erythematosus Disease Activity Index scores.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n CD8\n +<\/jats:sup>\n HLA\u2010DRB1\n +<\/jats:sup>\n T cells represent a dysfunctional effector memory and proliferative population expanded in SLE. Type I IFN drives this paradoxical state by promoting exhaustion and impairing degranulation.\n <\/jats:p>\n \n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/art.70292","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T15:50:11Z","timestamp":1786377011000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Type I Interferon Drives Dysfunction of a Distinct\n CD8<\/scp>\n +<\/sup>\n HLA<\/scp>\n \u2010\n DRB1<\/scp>\n +<\/sup>\n T Cell Subset in Systemic Lupus Erythematosus"],"prefix":"10.1002","author":[{"given":"Huizhong","family":"Long","sequence":"first","affiliation":[{"name":"Department of Orthopedics, Xiangya Hospital Central South University Changsha Hunan China"},{"name":"Division of Rheumatology, Department of Pediatrics, Children's Hospital of Pittsburgh University of Pittsburgh Pittsburgh Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elio","family":"Carmona","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Pediatrics, Children's Hospital of Pittsburgh University of Pittsburgh Pittsburgh Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikhail G.","family":"Dozmorov","sequence":"additional","affiliation":[{"name":"Department of Biostatistics Virginia Commonwealth University Richmond"},{"name":"Department of Pathology Virginia Commonwealth University Richmond"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3884-962X","authenticated-orcid":false,"given":"Amr H.","family":"Sawalha","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Pediatrics, Children's Hospital of Pittsburgh University of Pittsburgh Pittsburgh Pennsylvania"},{"name":"Division of Rheumatology and Clinical Immunology, Department of Medicine University of Pittsburgh Pittsburgh Pennsylvania"},{"name":"Lupus Center of Excellence University of Pittsburgh School of Medicine Pittsburgh Pennsylvania"},{"name":"Department of Immunology University of Pittsburgh Pittsburgh Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2022.108953"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2025.103441"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1100359"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00875"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.27408"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.27421"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119856"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(200105)44:5<1122:AID-ANR193>3.0.CO;2-D"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0102-3"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2013.06.004"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.40038"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)30485-9"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.12.014"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/acr2.11725"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0398-x"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2018-214323"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-0743-0"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.04.048"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.22139.1"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0619-0"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4402"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-018-4772-0"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xinn.2021.100141"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.11.043"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20019-0"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-53104-9"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-020-01990-9"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-1759(03)00265-5"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2021.556776"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1203217"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1136\/rmdopen-2024-005122"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1097\/BOR.0000000000000815"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.22654"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/cti2.1336"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI120859"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2025.102600"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0694-x"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rdc.2021.04.001"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1093\/cei\/uxae127"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22312-y"}],"container-title":["Arthritis & Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.70292","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/art.70292","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.70292","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T07:50:13Z","timestamp":1787730613000},"score":1,"resource":{"primary":{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/10.1002\/art.70292"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,26]]},"references-count":40,"alternative-id":["10.1002\/art.70292"],"URL":"https:\/\/doi.org\/10.1002\/art.70292","archive":["Portico"],"relation":{},"ISSN":["2326-5191","2326-5205"],"issn-type":[{"value":"2326-5191","type":"print"},{"value":"2326-5205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,26]]},"assertion":[{"value":"2026-01-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-28","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-26","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"art.70292"}}