title: Expression of programmed death-1 ligand (PD-L) 1, PD-L2, B7-H3, and inducible costimulator ligand on human respiratory tract epithelial cells and regulation by respiratory syncytial virus and type 1 and 2 cytokines.
abstract: BACKGROUND
  Respiratory syncytial virus (RSV) is associated with wheezing illness, and infections can occur repeatedly throughout life. We hypothesized that RSV infection of respiratory tract epithelial cells up-regulates B7 molecules that regulate memory immune responses and that type 1 and 2 cytokines differentially modulate this induction.
  
  
  METHODS
  We used flow-cytometric analysis to investigate programmed death-1 ligand (PD-L) 1, PD-L2, B7-H3, and inducible costimulatory ligand (ICOS-L) expression on tracheal (NCI-H292), bronchial (BEAS-2B), and alveolar (A549) epithelial cells; regulation of this expression by RSV, interferon (IFN)- gamma , and interleukin (IL)-4; and the effects of IFN-gamma and IL-4 on RSV-induced expression of these molecules.
  
  
  RESULTS
  B7-H3 was strongly expressed, PD-L1 and ICOS-L were moderately expressed, and PD-L2 was weakly expressed on unstimulated tracheal, bronchial, and alveolar epithelial cells. RSV infection up-regulated PD-L1, PD-L2, and B7-H3 expression on all cells and ICOS-L expression on bronchial and alveolar epithelial cells. IL-4 treatment alone had no effect, whereas IFN-gamma treatment alone increased PD-L1 and PD-L2 expression on all cells and decreased B7-H3 expression on bronchial and alveolar epithelial cells. On RSV-infected alevolar epithelial cells, IFN-gamma treatment increased PD-L1 and PD-L2 expression and decreased B7-H3 and ICOS-L expression, and IL-4 treatment increased PD-L2 and B7-H3 expression and decreased ICOS-L expression.
  
  
  CONCLUSIONS
  Respiratory tract epithelial cells express a wide range of B7 molecules. RSV infection increases their expression, and this expression is differentially regulated by IFN-gamma and IL-4. These processes may be involved in decreasing T cell antiviral immune responses to RSV and in RSV-associated wheezing.
authors.affiliation: Department of Respiratory Medicine, National Heart and Lung Institute, Imperial College London, UK.
authors.forename: Luminita A
authors.initials: LA
authors.lastname: Stanciu
authors.forename: Cinzia M
authors.initials: CM
authors.lastname: Bellettato
authors.forename: Vasile
authors.initials: V
authors.lastname: Laza-Stanca
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Coyle
authors.forename: Alberto
authors.initials: A
authors.lastname: Papi
authors.forename: Sebastian L
authors.initials: SL
authors.lastname: Johnston
mesh_terms: D015703:Antigens, CD; D060887:B7 Antigens; D018122:B7-1 Antigen / Q000378:metabolism; D060890:B7-H1 Antigen; D004847:Epithelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D060945:Inducible T-Cell Co-Stimulator Ligand; D036341:Intercellular Signaling Peptides and Proteins; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D015847:Interleukin-4 / Q000378:metabolism / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D061027:Programmed Cell Death 1 Ligand 2 Protein; D011506:Proteins; D011971:Receptors, Immunologic; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology*; D012136:Respiratory Syncytial Viruses / Q000276:immunology / Q000472:pathogenicity; D012137:Respiratory System / Q000166:cytology
chemical_list: D015703:Antigens, CD; D060887:B7 Antigens; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C423237:CD276 protein, human; C498514:ICOSLG protein, human; D060945:Inducible T-Cell Co-Stimulator Ligand; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C556977:PDCD1LG2 protein, human; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein; D011506:Proteins; D011971:Receptors, Immunologic; D015847:Interleukin-4; D007371:Interferon-gamma