title: Inhibitory molecules that regulate expansion and restoration of HCV-specific CD4+ T cells in patients with chronic infection.
abstract: OBJECTIVE
  Inhibitory receptors such as programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen (CTLA)-4 mediate CD8+ T-cell exhaustion during chronic viral infection, but little is known about roles in dysfunction of CD4+ T cells.
  
  
  METHODS
  We investigated the functions of inhibitory molecules on hepatitis C virus (HCV)-, influenza-, and Epstein-Barr virus (EBV)-specific CD4+ T cells in patients with chronic infections compared with patients with resolved HCV infection and healthy donors. Expression of PD-1, CTLA-4, CD305, and CD200R were analyzed on HCV-specific CD4+ T cells, isolated from peripheral blood using major histocompatibility complex class II tetramers. We investigated the effects of in vitro inhibition of various inhibitory pathways on proliferation and cytokine production by CD4+ T cells, and we compared these effects with those from inhibition of interleukin (IL)-10 and transforming growth factor (TGF)-β1.
  
  
  RESULTS
  PD-1 and CTLA-4 were up-regulated on virus-specific CD4+ T cells from patients with chronic HCV infections. PD-1 expression was lower on influenza- than on HCV-specific CD4+ T cells from subjects with chronic HCV infection, whereas CTLA-4 was expressed at similar levels, independent of their specificity. CD305 and CD200R were up-regulated in HCV resolvers. Blockade of PD-L1/2, IL-10, and TGF-β1 increased expansion of CD4+ T cells in patients with chronic HCV, whereas inhibition of IL-10 and TGF-β1 was most effective in restoring HCV-specific production of interferon gamma, IL-2, and tumor necrosis factor α.
  
  
  CONCLUSIONS
  We characterized expression of inhibitory molecules on HCV-, influenza-, and EBV-specific CD4+ T cells and the effects of in vitro blockade on CD4+ T-cell expansion and cytokine production. Inhibition of PD-1, IL-10, and TGF-β1 is most efficient in restoration of HCV-specific CD4+ T cells.
authors.affiliation: Medical Department II, University Hospital of Ludwig-Maximillians-University, and Institute for Immunology, Ludwig-Maximilians-University, Munich, Germany. bijan.raziorrouh@med.uni-muenchen.de
authors.forename: Bijan
authors.initials: B
authors.lastname: Raziorrouh
authors.forename: Axel
authors.initials: A
authors.lastname: Ulsenheimer
authors.forename: Winfried
authors.initials: W
authors.lastname: Schraut
authors.forename: Malte
authors.initials: M
authors.lastname: Heeg
authors.forename: Peter
authors.initials: P
authors.lastname: Kurktschiev
authors.forename: Reinhart
authors.initials: R
authors.lastname: Zachoval
authors.forename: Maria-Christina
authors.initials: MC
authors.lastname: Jung
authors.forename: Robert
authors.initials: R
authors.lastname: Thimme
authors.forename: Christoph
authors.initials: C
authors.lastname: Neumann-Haefelin
authors.forename: Sophia
authors.initials: S
authors.lastname: Horster
authors.forename: Martin
authors.initials: M
authors.lastname: Wächtler
authors.forename: Michael
authors.initials: M
authors.lastname: Spannagl
authors.forename: Jürgen
authors.initials: J
authors.lastname: Haas
authors.forename: Helmut M
authors.initials: HM
authors.lastname: Diepolder
authors.forename: Norbert H
authors.initials: NH
authors.lastname: Grüner
mesh_terms: D057134:Antibodies, Neutralizing; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D000954:Antigens, Surface / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D060908:CTLA-4 Antigen / Q000378:metabolism; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D005858:Germany; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000175:diagnosis / Q000276:immunology*; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D064446:Orexin Receptors; D009975:Orthomyxoviridae / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D012367:RNA, Viral / Q000097:blood; D011956:Receptors, Cell Surface / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019562:Viral Load
chemical_list: D057134:Antibodies, Neutralizing; D015703:Antigens, CD; D000954:Antigens, Surface; C477337:CD200R1 protein, human; D060908:CTLA-4 Antigen; C508609:IL10 protein, human; C508594:IL2 protein, human; D007376:Interleukin-2; D064446:Orexin Receptors; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D012367:RNA, Viral; D011956:Receptors, Cell Surface; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma