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While many aspects of immune dysfunction have been studied extensively in adult-onset SLE, there is limited and contradictory evidence of how cytotoxic CD8+ T cells contribute to disease pathogenesis and studies exploring cytotoxicity in JSLE are virtually non-existent. Here, we report that CD8+ T cell cytotoxic capacity is reduced in JSLE versus healthy controls, irrespective of treatment or disease activity. Transcriptomic and serum metabolomic analysis identified that this reduction in cytotoxic CD8+ T cells in JSLE was associated with upregulated type I interferon (IFN) signalling, mitochondrial dysfunction, and metabolic disturbances when compared to controls. Greater interrogation of the influence of these pathways on altered cytotoxic CD8+ T cell function demonstrated that JSLE CD8+ T cells had enlarged mitochondria and enhanced sensitivity to IFN-\u03b1 leading to selective apoptosis of effector memory (EM) CD8+ T cells, which are enriched for cytotoxic mediator-expressing cells. This process ultimately contributes to the observed reduction in CD8+ T cell cytotoxicity in JSLE, reinforcing the growing evidence that mitochondrial dysfunction is a key pathogenic factor affecting multiple immune cell populations in type I IFN-driven rheumatic diseases.<\/jats:p>","DOI":"10.1093\/cei\/uxae127","type":"journal-article","created":{"date-parts":[[2024,12,25]],"date-time":"2024-12-25T07:59:11Z","timestamp":1735113551000},"source":"Crossref","is-referenced-by-count":13,"title":["Type I interferon and mitochondrial dysfunction are associated with dysregulated cytotoxic CD8+ T cell responses in juvenile systemic lupus erythematosus"],"prefix":"10.1093","volume":"219","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3885-3477","authenticated-orcid":false,"given":"Anna","family":"Radziszewska","sequence":"first","affiliation":[{"name":"Centre for Adolescent Rheumatology Versus Arthritis at UCL, UCLH, GOSH , London ,","place":["UK"]},{"name":"Department of Ageing, Rheumatology & Regenerative Medicine, Division of Medicine, UCL , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Peckham","sequence":"additional","affiliation":[{"name":"Centre for Adolescent Rheumatology Versus Arthritis at UCL, UCLH, GOSH , London ,","place":["UK"]},{"name":"Department of Ageing, Rheumatology & Regenerative Medicine, Division of Medicine, UCL , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Restuadi","family":"Restuadi","sequence":"additional","affiliation":[{"name":"Centre for Adolescent Rheumatology Versus Arthritis at UCL, UCLH, GOSH , London ,","place":["UK"]},{"name":"Infection, Immunity and Inflammation Research & Teaching Department, UCL Great Ormond Street Institute of Child Health , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Kartawinata","sequence":"additional","affiliation":[{"name":"Centre for Adolescent Rheumatology Versus Arthritis at UCL, UCLH, GOSH , London ,","place":["UK"]},{"name":"Infection, Immunity and Inflammation Research & Teaching Department, UCL Great Ormond Street Institute of Child Health , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dale","family":"Moulding","sequence":"additional","affiliation":[{"name":"NIHR Biomedical Research Centre at Great Ormond Street Hospital , London ,","place":["UK"]},{"name":"Developmental Biology and Cancer Research & Teaching Department, UCL Great Ormond Street Institute of Child Health , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina M","family":"de Gruijter","sequence":"additional","affiliation":[{"name":"Centre for Adolescent Rheumatology Versus Arthritis at UCL, UCLH, GOSH , London ,","place":["UK"]},{"name":"Department of Ageing, Rheumatology & Regenerative Medicine, Division of Medicine, UCL , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7473-7652","authenticated-orcid":false,"given":"George A","family":"Robinson","sequence":"additional","affiliation":[{"name":"Centre for Adolescent Rheumatology Versus Arthritis at UCL, UCLH, GOSH , London ,","place":["UK"]},{"name":"Department of Ageing, Rheumatology & Regenerative Medicine, Division of Medicine, UCL , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam","family":"Butt","sequence":"additional","affiliation":[{"name":"Centre for Adolescent Rheumatology Versus Arthritis at UCL, UCLH, GOSH , London ,","place":["UK"]},{"name":"Department of Ageing, Rheumatology & Regenerative Medicine, Division of Medicine, UCL , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire T","family":"Deakin","sequence":"additional","affiliation":[{"name":"Centre for Adolescent Rheumatology Versus Arthritis at UCL, UCLH, GOSH , London ,","place":["UK"]},{"name":"Infection, Immunity and Inflammation Research & Teaching Department, UCL Great Ormond Street Institute of Child Health , London ,","place":["UK"]},{"name":"NIHR Biomedical Research Centre at Great Ormond Street Hospital , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7972-8066","authenticated-orcid":false,"given":"Meredyth G Ll","family":"Wilkinson","sequence":"additional","affiliation":[{"name":"Centre for Adolescent Rheumatology Versus Arthritis at UCL, UCLH, GOSH , London ,","place":["UK"]},{"name":"Infection, Immunity and Inflammation Research & Teaching Department, UCL Great Ormond Street Institute of Child Health , London ,","place":["UK"]},{"name":"NIHR Biomedical Research Centre at Great Ormond Street Hospital , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy R","family":"Wedderburn","sequence":"additional","affiliation":[{"name":"Centre for Adolescent Rheumatology Versus Arthritis at UCL, UCLH, GOSH , London ,","place":["UK"]},{"name":"Infection, Immunity and Inflammation Research & Teaching Department, UCL Great Ormond Street Institute of Child Health , London ,","place":["UK"]},{"name":"NIHR Biomedical Research Centre at Great Ormond Street Hospital , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2389-3396","authenticated-orcid":false,"given":"Elizabeth C","family":"Jury","sequence":"additional","affiliation":[{"name":"Department of Ageing, Rheumatology & Regenerative Medicine, Division of Medicine, UCL , London ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4800-4695","authenticated-orcid":false,"given":"Elizabeth C","family":"Rosser","sequence":"additional","affiliation":[{"name":"Centre for 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