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You are here: Home / Articles / New Insights into CD8+ T Cells & Lupus

New Insights into CD8+ T Cells & Lupus

July 6, 2021 • By Lara C. Pullen, PhD

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Multiple transcriptomic studies in systemic lupus erythematosus (SLE) cohorts have revealed that most patients with lupus have increased expression of type I interferon-stimulated genes. Accumulating evidence suggests that although acute type I interferon signaling improves immune response, prolonged signaling leads to regulatory pathways that limit immunity and promote chronic disease. This pattern may underscore the link between the transcriptome signature and the pathophysiology of lupus. Additional research indicates this interferon signature in patients with SLE is associated with defects in mitophagy.

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A new study demonstrates that exposure to type I interferon contributes to SLE pathogenesis via metabolic rewiring of CD8+ T cells. The findings by Norzawani Buang, PhD, research associate at Imperial College London, U.K., and colleagues indicate this metabolic rewiring promotes CD8+ T cell death. Their findings were published online on March 31 in Nature Communications.1

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The Findings

The investigators began their research by questioning whether T cell transcriptomic signatures could be used to determine disease activity in patients with SLE. They performed a comparative transcriptomic analysis of purified CD4+ and CD8+ T cells from patients with SLE and healthy controls. From this data, they created hierarchical clustering of all genes that were differentially expressed between healthy controls and patients with SLE. They found a relatively stronger association between gene expression signature and clinical parameters in CD8+ T cells than in CD4+ cells.

Closer examination of the CD8+ T cells from patients with lupus allowed the researchers to segregate patients into two groups based on the level of interferon-stimulated gene expression. When they compared the transcriptomic profiles between the two groups, they found the interferon-stimulated genes were differentially expressed; so, too, were the mitochondrial DNA oxidative phosphorylation genes. Patients with a high type I interferon signature (interferon-high) had reduced expression of mitochondria-encoded genes and mitochondria-associated metabolic pathways and tended to have a more severe disease course.

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The CD8+ T cells from interferon-High SLE patients also displayed increased mitochondrial size and membrane hyperpolarization compared with those from healthy controls and two other comparator groups (patients with interferon-negative SLE and patients with rheumatoid arthritis). These mitochondrial changes were most pronounced in the effector memory CD8+ T cells. The authors concluded from this finding that prolonged interferon-α exposure in patients with SLE may be triggering mitochondrial changes in CD8+, but not CD4+, T cells.

Next, the team evaluated the metabolic functions of the mitochondrial changes they detected in the CD8+ T cells from patients with interferon-high SLE, finding these cells had increased expression of two genes coding for well-known nicotinamide adenine dinucleotide (NAD+) consuming enzymes (CD38 and PARP). This finding further supported their hypothesis that the type I interferon signature was linked to dysregulation of the mitochondrial metabolism in CD8+ T cells. To test this hypothesis, they exposed CD8+ T cells from healthy volunteers to type I interferon and T cell receptor stimulation and were able to recreate the mitochondrial abnormalities seen in lupus patients. These SLE-like conditions increased CD8+ T cell NAD+ consumption and resulted in impaired respiration and reduced cell viability. When the investigators supplemented the cells with NAD+, they were able to reverse both conditions.

Clinical Implications

Rheumatologists have long wondered about the role of CD8+ T cells in lupus, says Donald E. Thomas Jr., MD, an associate professor of medicine at the Uniformed Services University of the Health Sciences, Bethesda, Md., and author of The Lupus Encyclopedia. Dr. Thomas, who is not affiliated with the study, looks forward to future research that may provide a more direct connection between the CD8+ T cells and regulatory T cells, which are often deficient in patients with lupus.

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Filed Under: Conditions, SLE (Lupus) Tagged With: CD8+ T Cells, SLE, SLE Resource Center, systemic lupus erythematosus (SLE)

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