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

Norzawani Buang,Marina Botto,Liz Lightstone,Alessandro Sardini,Victor Gray,Jacques Behmoaras,Guang Sheng Ling,Lunnathaya Tapeng,Chad Whilding,Matthew C Pickering,Thomas D Cairns

doi:10.1038/s41467-021-22312-y

Norzawani Buang, Marina Botto + Show 9 more

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https://doi.org/10.1038/s41467-021-22312-y

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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.

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The majority of patients with systemic lupus erythematosus (SLE) have high expression of type I IFN-stimulated genes
Using a combination of in silico and in vitro methods, here, we demonstrated that the metabolic rewiring observed in CD8+ T cells from SLE patients was the result of prolonged IFNα exposure and TCR stimulation
Under the persistent combination of these two stimuli, a condition probably unique to SLE patients, the CD8+ T cells displayed increased PARP gene expression associated with enhanced NAD+ consumption, reduced mitochondrial oxidative capacity and decreased survival (Fig. 7)

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Introduction

The majority of patients with systemic lupus erythematosus (SLE) have high expression of type I IFN-stimulated genes. 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. A large body of research has demonstrated that the majority of SLE patients have an increased expression of type I IFN-stimulated genes (ISGs), known as “IFN signature”[1]. Some studies have shown that type I IFNs downregulate mtDNA-encoded gene expression, reduce electron transport chain (ETC) activity and exert an antiproliferative effect in human B cell lines[13]

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