Metabolic programming of exhausted CD8+ T cells in chronic viral hepatitis

Accumulation of exhausted T cells (TEX) is a major concern in patients with chronic hepatitis B and C virus (HBV/HCV) infection. These TEX are characterized by the co-expression of inhibitory receptors, poor effector function and substantial changes in their transcriptional profile compared to functional T cells. Their functional impairment is thought to contribute to viral persistence. Recent evidence points to a central role for metabolic regulation in the development of TEX. We have recently demonstrated significant heterogeneity within virus-specific TEX in chronic viral infection.

This study aims to identify the metabolic pathways underlying the differentiation of CD127+ PD-1+ TEX with homeostatic precursor potential and more terminally exhausted CD127- PD-1+ subtypes of virus-specific TEX in patients with chronic HBV and HCV infection.

Glycolysis has been shown to be critical for T cell effector function whereas mitochondrial oxidative phosphorylation is crucial for long-term persistence of memory T cells. Mitochondrial and glycolytic properties were analyzed by flow cytometry. Metabolic pathways differentially regulated in either subset were further investigated following transcriptome profiling by gene-set enrichment analysis.

Interestingly, we observed that CD127+ PD-1+ TEX upregulated genes involved in glycolysis in contrast to the CD127- PD-1+ subset. This is in line with suppression of glycolysis mediated by inhibitory receptor signaling in more severe exhaustion. Functional testing revealed elevated glucose uptake in CD127+ PD-1+ TEX compared to CD127- PD-1+ cells, again suggesting restriction of glycolysis in more severe exhausted T cells. We then explored potential alternate nutrient sources for TEX that can provide intermediates of the tricarboxylic acid cycle in the setting of glucose restriction for their ability to revitalize TEX. We found that acetate which can enhance acetyl-CoA levels, improved T cell function in PD-1hi TEX isolated from HCV patients.

These results suggest that differential metabolic programming underlies the differentiation of diverse subtypes of virus-specific TEX in chronic infection. We are currently exploring the molecular mechanisms responsible for the regulation of TEX metabolism. Together, these data provide novel insights into the metabolic determinants of T cell exhaustion in human chronic viral infection and highlight pathways with therapeutic potential.