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

Exhausted T cells (T_EX) with limited function accumulate in chronic infections such as hepatitis B and -C virus infection. The prolonged exposure to viral antigen, the induction of co-inhibitory signals and the inflammatory milieu are thought to contribute to drive T_EX. T_EX are characterized by an increased inhibitory receptor expression and substantial alterations in their transcription profile. Regulation of energy metabolism has been suggested as a mechanism driving the dysfunction of exhausted T cells, however, the metabolic programming of HBV- and HCV-specific T cells in chronic infection and its links to T cell function remain unclear.

To address these important questions, we set out to profile key metabolic pathways involved in energy metabolism in patients with cHBV and cHCV using metabolism-directed flow cytometry and transcriptome profiling.

We found that in chronic infection, HCV-specific T cells display enhanced glucose uptake, but diminished mitochondrial polarization suggesting in comparison to HBV-specific T cells, a more severe type of exhaustion. Partial improvement of this phenotype was observed in patients with DAA therapy. Analysis of metabolic genes revealed an upregulation of ACSS1/ACSS2 mRNA encoding for acetyl-CoA synthetase in HCV-specific T cells, suggesting higher ability to metabolize acetate as a potential anaplerotic TCA substrate. In agreement with this notion, addition of acetate to exhausted CD8⁺ T cells from cHCV patients counteracted functional T cell exhaustion.

In sum, these results indicate that exhausted HBV- and HCV-specific CD8⁺ T cells exhibit differential metabolic programming. Detailed understanding of metabolic regulation may allow metabolism-directed interventions to improve T cell function.