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@ARTICLE{Winkler:277944,
      author       = {F. Winkler and A. V. Hipp and C. Ramirez and B. Martin and
                      M. Villa and E. Neuwirt and O. Gorka and J. Aerssens and S.
                      E. Johansson and N. Rana and S. Llewellyn-Lacey and D. A.
                      Price and M. Panning and O. Groß and E. L. Pearce and C. M.
                      Hermann and K. Schumann and L. Hannibal and C.
                      Neumann-Haefelin and T. Boettler and P. Knolle and M.
                      Hofmann and D. Wohlleber and R. Thimme and B. Bengsch$^*$},
      title        = {{E}nolase represents a metabolic checkpoint controlling the
                      differential exhaustion programmes of hepatitis
                      virus-specific {CD}8+ {T} cells.},
      journal      = {Gut},
      volume       = {72},
      number       = {10},
      issn         = {0017-5749},
      address      = {London},
      publisher    = {BMJ Publishing Group},
      reportid     = {DKFZ-2023-01587},
      pages        = {1971-1984},
      year         = {2023},
      note         = {2023 Oct;72(10):1971-1984},
      abstract     = {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.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.HBV-specific (core18-27, polymerase455-463) and
                      HCV-specific (NS31073-1081, NS31406-1415, NS5B2594-2602)
                      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 polymerase455-463 -specific CD8+ T cell
                      responses. In contrast, relative metabolic fitness was
                      observed in HBeAg-negative HBV infection in HBV
                      core18-27-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.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.},
      keywords     = {alpha beta T cells (Other) / chronic viral hepatitis
                      (Other) / hepatitis B (Other) / hepatitis C (Other) /
                      immunology in hepatology (Other)},
      cin          = {FR01},
      ddc          = {610},
      cid          = {I:(DE-He78)FR01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37541771},
      doi          = {10.1136/gutjnl-2022-328734},
      url          = {https://inrepo02.dkfz.de/record/277944},
}