The effects of type I interferons (IFN-Is) on immune cell metabolism
File(s)
Author(s)
Tapeng, Lunnathaya
Type
Thesis
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.
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.
Version
Open Access
Date Issued
2023-02
Date Awarded
2023-04
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Botto, Marina
Behmoaras, Jacques
Buang, Norzawani
Sponsor
Thailand
Publisher Department
Immunology and Inflammation
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)