Type I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
The majority of patients with systemic lupus erythematosus (SLE) have high expression of type I IFN-stimulated genes. Mitochondrial abnormalities have also been reported, but the contribution of type I IFN exposure to these changes is unknown. Here, we show downregulation of mitochondria-derived genes and mitochondria-associated metabolic pathways in IFN-High patients from transcriptomic analysis of CD4+ and CD8+ T cells. CD8+ T cells from these patients have enlarged mitochondria and lower spare respiratory capacity associated with increased cell death upon rechallenge with TCR stimulation. These mitochondrial abnormalities can be phenocopied by exposing CD8+ T cells from healthy volunteers to type I IFN and TCR stimulation. Mechanistically these ‘SLE-like’ conditions increase CD8+ T cell NAD+ consumption resulting in impaired mitochondrial respiration and reduced cell viability, both of which can be rectified by NAD+ supplementation. Our data suggest that type I IFN exposure contributes to SLE pathogenesis by promoting CD8+ T cell death via metabolic rewiring.
Date Issued
2021-03-31
Date Acceptance
2021-03-06
Citation
Nature Communications, 2021, 12 (1), pp.1-15
ISSN
2041-1723
Publisher
Nature Research
Start Page
1
End Page
15
Journal / Book Title
Nature Communications
Volume
12
Issue
1
Copyright Statement
© The Author(s) 2021. This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Sponsor
Wellcome Trust
Wellcome Trust
Medical Research Council (MRC)
Medical Research Council (MRC)
Medical Research Council (MRC)
Identifier
https://www.nature.com/articles/s41467-021-22312-y
Grant Number
108008/Z/15/Z
108008/Z/15/Z
MR/M004716/1
MR/N01121X/1
EP/V520354/1
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
Adult
Aged
CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
Cell Proliferation
Female
Gene Expression Profiling
Humans
Interferon Type I
Lupus Erythematosus, Systemic
Lymphocyte Activation
Metabolic Networks and Pathways
Middle Aged
Mitochondria
Young Adult
CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
Mitochondria
Humans
Lupus Erythematosus, Systemic
Interferon Type I
Gene Expression Profiling
Lymphocyte Activation
Cell Proliferation
Adult
Aged
Middle Aged
Female
Metabolic Networks and Pathways
Young Adult
Publication Status
Published online
Article Number
1980
Date Publish Online
2021-03-31