TY - JOUR
T1 - Enolase represents a metabolic checkpoint controlling the differential exhaustion programmes of hepatitis virus-specific CD8 + T cells
AU - Winkler, Frances
AU - Hipp, Anna V.
AU - Ramirez, Carlos
AU - Martin, Bianca
AU - Villa, Matteo
AU - Neuwirt, Emilia
AU - Gorka, Oliver
AU - Aerssens, Jeroen
AU - Johansson, Susanne E.
AU - Rana, Nisha
AU - Llewellyn-Lacey, Sian
AU - Price, David A.
AU - Panning, Marcus
AU - Groß, Olaf
AU - Pearce, Erika L.
AU - Hermann, Carl M.
AU - Schumann, Kathrin
AU - Hannibal, Luciana
AU - Neumann-Haefelin, Christoph
AU - Boettler, Tobias
AU - Knolle, Percy
AU - Hofmann, Maike
AU - Wohlleber, Dirk
AU - Thimme, Robert
AU - Bengsch, Bertram
N1 - Publisher Copyright:
© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.
PY - 2023/10/1
Y1 - 2023/10/1
N2 - Objective Exhausted T cells with limited effector function are enriched in chronic hepatitis B and C virus (HBV and HCV) infection. Metabolic regulation contributes to exhaustion, but it remains unclear how metabolism relates to different exhaustion states, is impacted by antiviral therapy, and if metabolic checkpoints regulate dysfunction. Design Metabolic state, exhaustion and transcriptome of virus-specific CD8 + T cells from chronic HBV-infected (n=31) and HCV-infected patients (n=52) were determined ex vivo and during direct-acting antiviral (DAA) therapy. Metabolic flux and metabolic checkpoints were tested in vitro. Intrahepatic virus-specific CD8 + T cells were analysed by scRNA-Seq in a HBV-replicating murine in vivo model of acute and chronic infection. Results HBV-specific (core 18-27, polymerase 455-463) and HCV-specific (NS3 1073-1081, NS3 1406-1415, NS5B 2594-2602) CD8 + T cell responses exhibit heterogeneous metabolic profiles connected to their exhaustion states. The metabolic state was connected to the exhaustion profile rather than the aetiology of infection. Mitochondrial impairment despite intact glucose uptake was prominent in severely exhausted T cells linked to elevated liver inflammation in chronic HCV infection and in HBV polymerase 455-463 -specific CD8 + T cell responses. In contrast, relative metabolic fitness was observed in HBeAg-negative HBV infection in HBV core 18-27 -specific responses. DAA therapy partially improved mitochondrial programmes in severely exhausted HCV-specific T cells and enriched metabolically fit precursors. We identified enolase as a metabolic checkpoint in exhausted T cells. Metabolic bypassing improved glycolysis and T cell effector function. Similarly, enolase deficiency was observed in intrahepatic HBV-specific CD8 + T cells in a murine model of chronic infection. Conclusion Metabolism of HBV-specific and HCV-specific T cells is strongly connected to their exhaustion severity. Our results highlight enolase as metabolic regulator of severely exhausted T cells. They connect differential bioenergetic fitness with distinct exhaustion subtypes and varying liver disease, with implications for therapeutic strategies.
AB - Objective Exhausted T cells with limited effector function are enriched in chronic hepatitis B and C virus (HBV and HCV) infection. Metabolic regulation contributes to exhaustion, but it remains unclear how metabolism relates to different exhaustion states, is impacted by antiviral therapy, and if metabolic checkpoints regulate dysfunction. Design Metabolic state, exhaustion and transcriptome of virus-specific CD8 + T cells from chronic HBV-infected (n=31) and HCV-infected patients (n=52) were determined ex vivo and during direct-acting antiviral (DAA) therapy. Metabolic flux and metabolic checkpoints were tested in vitro. Intrahepatic virus-specific CD8 + T cells were analysed by scRNA-Seq in a HBV-replicating murine in vivo model of acute and chronic infection. Results HBV-specific (core 18-27, polymerase 455-463) and HCV-specific (NS3 1073-1081, NS3 1406-1415, NS5B 2594-2602) CD8 + T cell responses exhibit heterogeneous metabolic profiles connected to their exhaustion states. The metabolic state was connected to the exhaustion profile rather than the aetiology of infection. Mitochondrial impairment despite intact glucose uptake was prominent in severely exhausted T cells linked to elevated liver inflammation in chronic HCV infection and in HBV polymerase 455-463 -specific CD8 + T cell responses. In contrast, relative metabolic fitness was observed in HBeAg-negative HBV infection in HBV core 18-27 -specific responses. DAA therapy partially improved mitochondrial programmes in severely exhausted HCV-specific T cells and enriched metabolically fit precursors. We identified enolase as a metabolic checkpoint in exhausted T cells. Metabolic bypassing improved glycolysis and T cell effector function. Similarly, enolase deficiency was observed in intrahepatic HBV-specific CD8 + T cells in a murine model of chronic infection. Conclusion Metabolism of HBV-specific and HCV-specific T cells is strongly connected to their exhaustion severity. Our results highlight enolase as metabolic regulator of severely exhausted T cells. They connect differential bioenergetic fitness with distinct exhaustion subtypes and varying liver disease, with implications for therapeutic strategies.
KW - alpha beta T cells
KW - chronic viral hepatitis
KW - hepatitis B
KW - hepatitis C
KW - immunology in hepatology
UR - http://www.scopus.com/inward/record.url?scp=85168262212&partnerID=8YFLogxK
U2 - 10.1136/gutjnl-2022-328734
DO - 10.1136/gutjnl-2022-328734
M3 - Article
C2 - 37541771
AN - SCOPUS:85168262212
SN - 0017-5749
VL - 72
SP - 1971
EP - 1984
JO - Gut
JF - Gut
IS - 10
ER -