Exhausted T cells (TEX) 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 TEX. TEX 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.
