The effects of type I interferons (IFN-Is) on immune cell metabolism

Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterised by the formation of immune complexes that, when deposited in tissues, can cause damage. Type I interferons (IFN-Is) are thought to be a major driver of SLE pathogenesis, but the underlying mechanism(s) remains elusive. Emerging literature has shown that PBMCs and CD4+ T cells from SLE patients display an abnormal metabolic status that can lead to aberrant T cell activation and impaired cell death pathways, causing further immune dysregulation. However, the link between the metabolic changes observed in the immune cells of SLE patients and the IFN-I signature remains unclear. Preliminary findings from my host laboratory using RNA-sequencing analysis of CD8+ T cells from SLE patients showed a potential link between the IFN-I signature and an abnormal CD8+ T cell metabolism. These preliminary data and the knowledge gap in the literature inspired me to investigate the effects of chronic IFN-I exposure on mitochondrial metabolism and functions of CD8+ T cells and macrophages, two key immune cells in lupus pathogenesis. To achieve this, I treated PBMCs, CD8+ T cells and macrophages from healthy donors with IFN-α for several days and performed transcriptomic, metabolic and functional analyses. Using these experimental conditions, I found that in CD8+ T cells only the combination of IFN-α and TCR stimulation triggered the same abnormal mitochondrial features (e.g increased mitochondrial mass and activity and reduced spare respiratory capacity) seen in SLE patients with a high IFN-I signature. Further functional analyses also revealed that the combination of chronic IFN-I exposure and TCR activation led to an increased cell death upon antigen rechallenge. On the other hand, in macrophages chronic IFN-I exposure induced a striking metabolic reprogramming characterised by increased NAD consumption and activation of tryptophan pathways. Furthermore, chronic IFN-I exposure promoted a unique pro-inflammatory phenotype with increased CD38, CD80 and IL-6 expression and induced cell death in response to TLR4 stimulation but no to other TLR triggers. These IFN-I-induced changes in macrophages were mediated by CD38, a NAD-consuming enzyme, possibly via activation of the tryptophan pathway. Inhibition of CD38 or deficiency of tryptophan was able to rectify the IFN-I-mediated pro-inflammatory phenotype and the LPS-induced cell death. Taken together, the data suggest that chronic IFN-α exposure affects the mitochondrial metabolism in CD8+ T cells and macrophages differently, leading to abnormal immune functions.