{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T09:22:37Z","timestamp":1767691357468,"version":"3.48.0"},"posted":{"date-parts":[[2026,1,3]]},"group-title":"Rheumatology","reference-count":32,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,3]],"date-time":"2026-01-03T00:00:00Z","timestamp":1767398400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>\n                    Systemic lupus erythematosus (SLE) is characterized by persistent type I interferon (IFN) signaling and adaptive immune dysregulation. We previously identified hypomethylation of\n                    <jats:italic>HLA-DRB1<\/jats:italic>\n                    and\n                    <jats:italic>STAT1<\/jats:italic>\n                    in SLE CD8+ T cells, enabling aberrant IFN-driven HLA-DRB1 expression and expansion of a distinct CD8+ T cell subset. This study aimed to comprehensively characterize CD8+ HLA-DRB1+ T cells in lupus.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Peripheral blood CD8+ T cells from SLE patients and healthy controls were analyzed by flow cytometry to assess differentiation and effector functions. Single-cell RNA sequencing and TCR sequencing, with and without IFN-\u03b1 stimulation, were used to assess transcriptional heterogeneity, exhaustion, senescence, and cytotoxicity.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>CD8+ HLA-DRB1+ T cells were enriched within effector memory and terminally differentiated CD8+ T cells and were significantly expanded within the effector memory compartment in SLE compared to healthy controls. These cells displayed paradoxical features of cytotoxic activation, proliferative potential, exhaustion, and senescence. Compared to healthy controls, lupus CD8+ HLA-DRB1+ T cells exhibited increased exhaustion, reduced cytotoxicity, and impaired viral defense pathways. IFN-\u03b1 treatment enhanced IFN-\u03b3 responses in lupus CD8+ HLA-DRB1+ T cells and exacerbated exhaustion and senescence. Despite upregulation of cytotoxic gene expression, IFN-\u03b1 reduced CD107a surface mobilization, indicating impaired degranulation. Analysis of lupus nephritis datasets revealed that most kidney-infiltrating CD8+ T cells express HLA-DRB1.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>CD8+ HLA-DRB1+ T cells represent a cytotoxic yet dysfunctional effector memory population expanded in SLE. Type I IFN drives this paradoxical state by promoting exhaustion and impaired degranulation, highlighting a potential therapeutic axis in SLE.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.01.02.26343348","type":"posted-content","created":{"date-parts":[[2026,1,4]],"date-time":"2026-01-04T01:40:11Z","timestamp":1767490811000},"source":"Crossref","is-referenced-by-count":0,"title":["Type I interferon drives dysfunction of a distinct CD8+ HLA-DRB1+ T cell subset in systemic lupus erythematosus"],"prefix":"10.64898","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\u2019s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elio","family":"Carmona","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Pediatrics, Children\u2019s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mikhail G","family":"Dozmorov","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia, USA"},{"name":"Department of Pathology, Virginia Commonwealth University, Richmond, Virginia, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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\u2019s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania, USA"},{"name":"Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA"},{"name":"Lupus Center of Excellence, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"},{"name":"Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026010601200592000_2026.01.02.26343348v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2022.108953"},{"key":"2026010601200592000_2026.01.02.26343348v1.2","doi-asserted-by":"crossref","first-page":"103441","DOI":"10.1016\/j.jaut.2025.103441","article-title":"Integrated analysis of polygenic and environmental risk scores for late-onset systemic lupus erythematosus","volume":"154","year":"2025","journal-title":"J Autoimmun"},{"key":"2026010601200592000_2026.01.02.26343348v1.3","doi-asserted-by":"crossref","first-page":"875","DOI":"10.3389\/fimmu.2018.00875","article-title":"Deoxyribonucleic Acid Methylation in Systemic Lupus Erythematosus: Implications for Future Clinical Practice","volume":"9","year":"2018","journal-title":"Front Immunol"},{"key":"2026010601200592000_2026.01.02.26343348v1.4","doi-asserted-by":"publisher","DOI":"10.1002\/art.27408"},{"issue":"6","key":"2026010601200592000_2026.01.02.26343348v1.5","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1002\/art.27421","article-title":"Everyone comes from somewhere: systemic lupus erythematosus and Epstein-Barr virus induction of host interferon and humoral anti-Epstein-Barr nuclear antigen 1 immunity","volume":"62","year":"2010","journal-title":"Arthritis Rheum"},{"key":"2026010601200592000_2026.01.02.26343348v1.6","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119856"},{"key":"2026010601200592000_2026.01.02.26343348v1.7","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(200105)44:5<1122::AID-ANR193>3.0.CO;2-D"},{"key":"2026010601200592000_2026.01.02.26343348v1.8","doi-asserted-by":"crossref","unstructured":"Harley JB , Chen X , Pujato M , Miller D , Maddox A , Forney C , et al. 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