TY  - INPR
Y1  - 2025/12/25/
AV  - public
TI  - Type I interferon and mitochondrial dysfunction are associated with dysregulated cytotoxic CD8+ T cell responses in juvenile systemic lupus erythematosus
N1  - © 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.
UR  - https://doi.org/10.1093/cei/uxae127
ID  - discovery10202708
N2  - 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-? 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.
KW  - CD8+ T cells
KW  -  cytotoxicity
KW  -  juvenile systemic lupus erythematosus
KW  -  interferon
A1  - Radziszewska, Ania
A1  - Peckham, Hannah
A1  - Restuadi, Restuadi
A1  - Kartawinata, Melissa
A1  - Moulding, Dale
A1  - De Gruijter, Nina
A1  - Robinson, George A
A1  - Butt, Maryam
A1  - Deakin, Claire
A1  - Wilkinson, Meredyth
A1  - Wedderburn, Lucy
A1  - Jury, Elizabeth
A1  - Rosser, Elizabeth
A1  - Ciurtin, Coziana
JF  - Clinical and Experimental Immunology
ER  -