Enolase represents a metabolic checkpoint controlling the differential exhaustion of virus-specific CD8+ T cells in viral hepatitis

Exhausted T cells (TEX) accumulating in patients with chronic Hepatitis B and -C virus (HBV/HCV) infection are functionally impaired and contribute to insufficient virus elimination. There is recent evidence that a dysregulated energy metabolism is a major driver in the development of T cell exhaustion. However, the connection of the metabolic profiles and antiviral function of HBV- and HCV-specific CD8+ T cells in chronic infection remains poorly adressed. Therefore, we analyzed the metabolic determinants of HBV- and HCV-specific CD8+ T cells by flow cytometry and peformed microarray analysis of sorted HBV- and HCV-specific CD8+ T cells to analyze key metabolic pathways. We found that in chronic infection, HCV-specific CD8+ T cells exhibit reduced mitochondrial polarization associated with increased expression of inhibitory receptors, suggesting that these cells are more profoundly exhausted compared to HBV-specific CD8+ T cells. Metabolic pathway analysis revealed downregulation of the ENO1 mRNA transcripts in HCV-specific CD8+ T cells, suggesting that diversion of metabolic flux during glycolysis represents a metabolic checkpoint for exhausted CD8+ T cells. Bypassing this bottleneck by supplementation of pyruvate bolsters antiviral function of HCV-specific CD8+ T cells. Taken together, these results reveal distinct metabolic programs of exhausted HBV- and HCV-specific CD8+ T cells. They demonstrate that metabolic interventions are useful strategies to improve T cell function in chronic viral infections. Publication History Article published online: 26 January 2022 © 2022. Thieme. All rights reserved. Georg Thieme Verlag Rüdigerstraße 14, 70469 Stuttgart, Germany