title: Combined blockade of programmed death-1 and activation of CD137 increase responses of human liver T cells against HBV, but not HCV.
abstract: OBJECTIVE
  In patients with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, antiviral functions of T cells are impaired; these might be increased by blocking T-cell co-inhibitory pathways, such as preventing interaction between the receptor programmed death (PD)-1 and its ligand, PD-L1. We attempted to optimize the restoration of T-cell functions in patients with chronic HBV or HCV infection with a combination of reagents that block PD-1 interaction with PD-L1 and stimulate T-cell signaling via CD137, a member of the tumor necrosis factor-receptor family.
  
  
  METHODS
  We assessed the effects of CD137 stimulation (via CD137L), alone or in combination with antibodies that block PD-1 interaction with PD-L1 (anti-PD-L1), on proliferation and production of interferon-γ and interleukin-2 by intrahepatic and peripheral T cells from patients with chronic HBV or HCV infection. We also analyzed expression of different co-stimulatory molecules on virus-specific CD8+ and forkhead box P3+CD4+ cells by flow cytometry.
  
  
  RESULTS
  Incubation of intrahepatic T cells with CD137L and anti-PD-L1 increased their responses to HBV, but not HCV. However, HCV-specific T cells isolated from peripheral blood were sensitive to these reagents. Virus-specific T cells from some, but not all patients, had increased responses to anti-PD-L1 when CD137L was added because in some cases the combination of anti-PD-L1 and CD137L overstimulated T cells, leading to their inhibition. Intrahepatic HBV- and HCV-specific CD8+ T cells had different costimulatory profiles; liver cells from patients with chronic HBV infection had a higher proportion of forkhead box P3+ regulatory T cells, with higher levels of PD-1, compared with liver cells from patients with chronic HCV infection.
  
  
  CONCLUSIONS
  A combination of reagents that prevent interaction between PD-1 and its ligand and activate CD137 signaling increase responses of intrahepatic HBV-specific T cells and circulating HCV-specific T cells. This strategy might be developed to increase T-cell responses to these viruses in patients with chronic hepatitis B or C, and tailoring the dose of CD137L administered will help optimize results.
authors.affiliation: Laboratory of Viral Immunopathology, Unit of Infectious Diseases and Hepatology, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Fisicaro
authors.forename: Caterina
authors.initials: C
authors.lastname: Valdatta
authors.forename: Marco
authors.initials: M
authors.lastname: Massari
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Loggi
authors.forename: Lara
authors.initials: L
authors.lastname: Ravanetti
authors.forename: Simona
authors.initials: S
authors.lastname: Urbani
authors.forename: Tiziana
authors.initials: T
authors.lastname: Giuberti
authors.forename: Albertina
authors.initials: A
authors.lastname: Cavalli
authors.forename: Carmen
authors.initials: C
authors.lastname: Vandelli
authors.forename: Pietro
authors.initials: P
authors.lastname: Andreone
authors.forename: Gabriele
authors.initials: G
authors.lastname: Missale
authors.forename: Carlo
authors.initials: C
authors.lastname: Ferrari
mesh_terms: D000328:Adult; D000368:Aged; D000906:Antibodies / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D016174:Hepacivirus / Q000502:physiology*; D006515:Hepatitis B virus / Q000502:physiology*; D019694:Hepatitis B, Chronic / Q000378:metabolism / Q000473:pathology; D019698:Hepatitis C, Chronic / Q000378:metabolism / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008024:Ligands; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000502:physiology*
chemical_list: D000906:Antibodies; D007376:Interleukin-2; D008024:Ligands; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D007371:Interferon-gamma