eprintid: 10202708 rev_number: 11 eprint_status: archive userid: 699 dir: disk0/10/20/27/08 datestamp: 2025-01-03 14:01:52 lastmod: 2025-01-03 14:01:52 status_changed: 2025-01-03 14:01:52 type: article metadata_visibility: show sword_depositor: 699 creators_name: Radziszewska, Ania creators_name: Peckham, Hannah creators_name: Restuadi, Restuadi creators_name: Kartawinata, Melissa creators_name: Moulding, Dale creators_name: De Gruijter, Nina creators_name: Robinson, George A creators_name: Butt, Maryam creators_name: Deakin, Claire creators_name: Wilkinson, Meredyth creators_name: Wedderburn, Lucy creators_name: Jury, Elizabeth creators_name: Rosser, Elizabeth creators_name: Ciurtin, Coziana title: Type I interferon and mitochondrial dysfunction are associated with dysregulated cytotoxic CD8+ T cell responses in juvenile systemic lupus erythematosus ispublished: inpress divisions: UCL divisions: B02 divisions: C10 keywords: CD8+ T cells, cytotoxicity, juvenile systemic lupus erythematosus, interferon note: © The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. abstract: Juvenile systemic lupus erythematosus (JSLE) is an autoimmune condition which causes significant morbidity in children and young adults and is more severe in its presentation than adult-onset SLE. 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-α 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. date: 2025-12-25 date_type: published official_url: https://doi.org/10.1093/cei/uxae127 oa_status: green full_text_type: other language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 2344501 doi: 10.1093/cei/uxae127 lyricists_name: Ciurtin, Coziana lyricists_id: CCIUR23 actors_name: Ciurtin, Coziana actors_id: CCIUR23 actors_role: owner full_text_status: public publication: Clinical and Experimental Immunology article_number: uxae127 citation: Radziszewska, Ania; Peckham, Hannah; Restuadi, Restuadi; Kartawinata, Melissa; Moulding, Dale; De Gruijter, Nina; Robinson, George A; ... Ciurtin, Coziana; + view all <#> Radziszewska, Ania; Peckham, Hannah; Restuadi, Restuadi; Kartawinata, Melissa; Moulding, Dale; De Gruijter, Nina; Robinson, George A; Butt, Maryam; Deakin, Claire; Wilkinson, Meredyth; Wedderburn, Lucy; Jury, Elizabeth; Rosser, Elizabeth; Ciurtin, Coziana; - view fewer <#> (2025) Type I interferon and mitochondrial dysfunction are associated with dysregulated cytotoxic CD8+ T cell responses in juvenile systemic lupus erythematosus. Clinical and Experimental Immunology , Article uxae127. 10.1093/cei/uxae127 <https://doi.org/10.1093/cei%2Fuxae127>. (In press). Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10202708/1/Ciurtin_uxae127.pdf