title: Restoration of HBV-specific CD8+ T cell function by PD-1 blockade in inactive carrier patients is linked to T cell differentiation.
abstract: OBJECTIVE
  The upregulation of several inhibitory signalling pathways by exhausted HBV-specific CD8+ T cells in chronic infection is thought to contribute to viral persistence. Blockade of inhibitory receptors to reinvigorate exhausted T cell function is a promising novel therapeutic approach. However, little information is available regarding the relative contribution of individual inhibitory pathways to HBV-specific CD8+ T cell failure and the impact of inhibitory receptor blockade on restoration of T cell function in chronic HBV.
  
  
  METHODS
  98 HLA-A2+ chronically infected patients were analysed ex vivo for HBV-specific CD8+ T cell responses, the expression of multiple inhibitory receptors and T cell differentiation markers. The effects of inhibitory receptor blockade targeting PD-1, 2B4, Tim-3, CTLA-4, and BTLA were assessed in vitro.
  
  
  RESULTS
  In our cohort, ex vivo HBV-specific CD8+ T cell responses were identified preferentially in HBeAg patients with low ALT and low viral load (inactive carriers). We observed a clear hierarchy of inhibitory receptor expression dominated by PD-1. The response to inhibitory receptor blockade was heterogeneous. Compared to the blockade of other inhibitory receptors, blockade of the PD-1 pathway resulted in the strongest increase in function. Of note, a positive effect of PD-1 blockade was linked to intermediate T cell differentiation.
  
  
  CONCLUSIONS
  Despite the expression of multiple inhibitory receptors by HBV-specific CD8+ T cells, expression and response to blockade was dominated by PD-1. However, PD-1 expression did not predict response to blockade. Rather, response to blockade was associated with intermediate T cell differentiation. These findings have important implications for our understanding of inhibitory receptor blockade as a novel therapeutic strategy.
authors.affiliation: Department of Medicine II, University Hospital of Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Germany; Faculty of Biology, University of Freiburg, Germany.
authors.forename: Bertram
authors.initials: B
authors.lastname: Bengsch
authors.affiliation: Department of Medicine II, University Hospital of Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Germany; Faculty of Biology, University of Freiburg, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Martin
authors.affiliation: Department of Medicine II, University Hospital of Freiburg, Germany. Electronic address: Robert.Thimme@uniklinik-freiburg.de.
authors.forename: Robert
authors.initials: R
authors.lastname: Thimme
mesh_terms: D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000378:metabolism; D000906:Antibodies / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D006509:Hepatitis B / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006513:Hepatitis B e Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D019562:Viral Load / Q000502:physiology
chemical_list: D000906:Antibodies; D006513:Hepatitis B e Antigens; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000410:Alanine Transaminase
keywords: HBV; Inactive carrier; Inhibitory receptors; PD-1; T cell differentiation; T cell exhaustion; Virus-specific CD8+ T cells