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

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. Lupus pathogenesis is associated with high type 1 interferon stimulated gene (ISG) expression. Here, the authors correlate ISG expression in CD8(+) T cells from lupus nephritis patients with abnormal mitochondrial function, implicating increased NAD consumption and reduced cell viability in the pathogenesis.

Automated summary

This study reveals that high expression of type I interferon in SLE patients affects mitochondrial function and cell metabolism in CD8(+) T cells, leading to cell death. Furthermore, these abnormalities can be corrected by NAD+ supplementation.