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Type I interferons affect the metabolic fitness of CD8⁺ T cells from patients with systemic lupus erythematosus.

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.

SUBMITTER: Buang N

PROVIDER: S-EPMC8012390 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Type I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus.

Buang Norzawani N Tapeng Lunnathaya L Gray Victor V Sardini Alessandro A Whilding Chad C Lightstone Liz L Cairns Thomas D TD Pickering Matthew C MC Behmoaras Jacques J Ling Guang Sheng GS Botto Marina M

Nature communications 20210331 1

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 enl ...[more]

PMID: 33790300

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Project description:BackgroundSystemic lupus erythematosus (SLE) is a prototypical autoimmune disease affecting multiple organs and tissues with high cellular heterogeneity. CD8+ T cell activity is involved in the SLE pathogenesis. However, the cellular heterogeneity and the underlying mechanisms of CD8+ T cells in SLE remain to be identified.MethodsSingle-cell RNA sequencing (scRNA-seq) of PBMCs from a SLE family pedigree (including 3 HCs and 2 SLE patients) was performed to identify the SLE-associated CD8+ T cell subsets. Flow cytometry analysis of a SLE cohort (including 23 HCs and 33 SLE patients), qPCR analysis of another SLE cohort (including 30 HCs and 25 SLE patients) and public scRNA-seq datasets of autoimmune diseases were employed to validate the finding. Whole-exome sequencing (WES) of this SLE family pedigree was used to investigate the genetic basis in dysregulation of CD8+ T cell subsets identified in this study. Co-culture experiments were performed to analyze the activity of CD8+ T cells.FindingsWe elucidated the cellular heterogeneity of SLE and identified a new highly cytotoxic CD8+ T cell subset, CD161-CD8+ TEMRA cell subpopulation, which was remarkably increased in SLE patients. Meanwhile, we discovered a close correlation between mutation of DTHD1 and the abnormal accumulation of CD161-CD8+ TEMRA cells in SLE. DTHD1 interacted with MYD88 to suppress its activity in T cells and DTHD1 mutation promoted MYD88-dependent pathway and subsequently increased the proliferation and cytotoxicity of CD161-CD8+ TEMRA cells. Furthermore, the differentially expressed genes in CD161-CD8+ TEMRA cells displayed a strong out-of-sample prediction for case-control status of SLE.InterpretationThis study identified DTHD1-associated expansion of CD161-CD8+ TEMRA cell subpopulation is critical for SLE. Our study highlights genetic association and cellular heterogeneity of SLE pathogenesis and provides a mechanistical insight into the diagnosis and treatment of SLE.FundingsStated in the Acknowledgements section of the manuscript.

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Type I interferons affect the metabolic fitness of CD8⁺ T cells from patients with systemic lupus erythematosus.

Publications

Type I interferons affect the metabolic fitness of CD8<sup>+</sup> T cells from patients with systemic lupus erythematosus.

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Type I interferons affect the metabolic fitness of CD8+ T cells from patients with systemic lupus erythematosus.

Publications

Type I interferons affect the metabolic fitness of CD8&lt;sup&gt;+&lt;/sup&gt; T cells from patients with systemic lupus erythematosus.

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OmicsDI is part of the ELIXIR infrastructure

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Type I interferons affect the metabolic fitness of CD8⁺ T cells from patients with systemic lupus erythematosus.

Type I interferons affect the metabolic fitness of CD8<sup>+</sup> T cells from patients with systemic lupus erythematosus.