title: Inhibitory phenotype of HBV-specific CD4+ T-cells is characterized by high PD-1 expression but absent coregulation of multiple inhibitory molecules.
abstract: BACKGROUND
  T-cell exhaustion seems to play a critical role in CD8+ T-cell dysfunction during chronic viral infections. However, up to now little is known about the mechanisms underlying CD4+ T-cell dysfunction during chronic hepatitis B virus (CHB) infection and the role of inhibitory molecules such as programmed death 1 (PD-1) for CD4+ T-cell failure.
  
  
  METHODS
  The expression of multiple inhibitory molecules such as PD-1, CTLA-4, TIM-3, CD244, KLRG1 and markers defining the grade of T-cell differentiation as CCR7, CD45RA, CD57 and CD127 were analyzed on virus-specific CD4+ T-cells from peripheral blood using a newly established DRB1*01-restricted MHC class II Tetramer. Effects of in vitro PD-L1/2 blockade were defined by investigating changes in CD4+ T-cell proliferation and cytokine production.
  
  
  RESULTS
  CD4+ T-cell responses during chronic HBV infection was characterized by reduced Tetramer+CD4+ T-cell frequencies, effector memory phenotype, sustained PD-1 but low levels of CTLA-4, TIM-3, KLRG1 and CD244 expression. PD-1 blockade revealed individualized patterns of in vitro responsiveness with partly increased IFN-γ, IL-2 and TNF-α secretion as well as enhanced CD4+ T-cell expansion almost in treated patients with viral control.
  
  
  CONCLUSIONS
  HBV-specific CD4+ T-cells are reliably detectable during different courses of HBV infection by MHC class II Tetramer technology. CD4+ T-cell dysfunction during chronic HBV is basically linked to strong PD-1 upregulation but absent coregulation of multiple inhibitory receptors. PD-L1/2 neutralization partly leads to enhanced CD4+ T-cell functionality with heterogeneous patterns of CD4+ T-cell rejunivation.
authors.affiliation: Medical Department II and Institute for Immunology, University of LMU Munich, Munich, Germany.
authors.forename: Bijan
authors.initials: B
authors.lastname: Raziorrouh
authors.affiliation: Medical Department II and Institute for Immunology, University of LMU Munich, Munich, Germany; Department of Nephrology/Rheumatology, University of Göttingen, Göttingen, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Heeg
authors.affiliation: Medical Department II and Institute for Immunology, University of LMU Munich, Munich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kurktschiev
authors.affiliation: Medical Department II and Institute for Immunology, University of LMU Munich, Munich, Germany.
authors.forename: Winfried
authors.initials: W
authors.lastname: Schraut
authors.affiliation: Medical Department II and Institute for Immunology, University of LMU Munich, Munich, Germany.
authors.forename: Reinhart
authors.initials: R
authors.lastname: Zachoval
authors.affiliation: Medical Department, Klinikum München-Schwabing, Munich, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Wendtner
authors.affiliation: Medical Department, Klinikum München-Schwabing, Munich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Wächtler
authors.affiliation: Laboratory of Immunogenetics/Molecular Diagnostics, University of LMU Munich, Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Spannagl
authors.affiliation: Medical Department II and Institute for Immunology, University of LMU Munich, Munich, Germany.
authors.forename: Gerald
authors.initials: G
authors.lastname: Denk
authors.affiliation: Medical Department II and Institute for Immunology, University of LMU Munich, Munich, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Ulsenheimer
authors.affiliation: Medical Department II, University of Freiburg, Freiburg, Germany.
authors.forename: Bertram
authors.initials: B
authors.lastname: Bengsch
authors.affiliation: Department of Immunology, University of Freiburg, Freiburg, Germany.
authors.forename: Hanspeter
authors.initials: H
authors.lastname: Pircher
authors.affiliation: Medical Department II and Institute for Immunology, University of LMU Munich, Munich, Germany.
authors.forename: Helmut M
authors.initials: HM
authors.lastname: Diepolder
authors.affiliation: Medical Department II and Institute for Immunology, University of LMU Munich, Munich, Germany.
authors.forename: Norbert H
authors.initials: NH
authors.lastname: Grüner
authors.affiliation: Leberzentrum, Munich, Germany.
authors.forename: Maria-Christina
authors.initials: MC
authors.lastname: Jung
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D061025:Costimulatory and Inhibitory T-Cell Receptors / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000276:immunology* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology*
chemical_list: D061025:Costimulatory and Inhibitory T-Cell Receptors; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor