title: Tolerogenic signaling by pulmonary CD1c+ dendritic cells induces regulatory T cells in patients with chronic obstructive pulmonary disease by IL-27/IL-10/inducible costimulator ligand.
abstract: BACKGROUND
  Increased mortality rates in patients with chronic obstructive pulmonary disease (COPD) are largely due to severe infectious exacerbations. Impaired respiratory immunity is linked to the enhanced susceptibility to infections. Dendritic cells (DCs) direct host immune responses toward immunity or tolerance. Pulmonary CD1c(+) DCs elicit robust antiviral immune responses in healthy subjects. Nevertheless, their functional specialization in patients with COPD remains unexplored.
  
  
  OBJECTIVE
  We sought to better understand the mechanisms that suppress respiratory immunity in patients with COPD by examining the immunostimulatory and tolerogenic properties of pulmonary CD1c(+) DCs.
  
  
  METHODS
  We analyzed the expression of costimulatory and tolerogenic molecules by pulmonary CD1c(+) DCs from patients with COPD (CD1c(+)DCCOPD) and former smokers without COPD. We isolated lung CD1c(+) DCs and determined their ability to stimulate allogeneic T-cell responses. The suppressive effects of lung CD1c(+) DCs and CD1c(+) DC-primed T cells on mixed leukocyte reactions were examined. An experimental human model of COPD exacerbation was used to investigate the levels of critical immunosuppressive molecules in vivo.
  
  
  RESULTS
  CD1c(+) DCs from patients with COPD hinder T-cell effector functions and favor the generation of suppressive IL-10-secreting CD4(+) T cells that function through IL-10 and TGF-β. IL-27, IL-10, and inducible T-cell costimulator ligand signaling are essential for CD1c(+)DCCOPD-mediated differentiation of IL-10-producing suppressive T cells. Exposure of lung CD1c(+) DCs from nonobstructed subjects to lungs of patients with COPD confers tolerogenic properties. IL-27 and IL-10 levels are increased in the lung microenvironment on rhinovirus-induced COPD exacerbation in vivo.
  
  
  CONCLUSIONS
  We identify a novel tolerogenic circuit encompassing suppressive CD1c(+) DCs and regulatory T cells in patients with COPD that might be implicated in impaired respiratory immunity and further highlight IL-10 and IL-27 as potent therapeutic targets.
authors: First Department of Intensive Care Medicine, Evaggelismos Hospital, University of Athens Medical School, Athens, Greece. Electronic address: tsoumak@yahoo.gr.
authors: Maria
authors: M
authors: Tsoumakidou
authors: Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors: Sofia
authors: S
authors: Tousa
authors: Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors: Maria
authors: M
authors: Semitekolou
authors: First Department of Intensive Care Medicine, Evaggelismos Hospital, University of Athens Medical School, Athens, Greece.
authors: Panagiota
authors: P
authors: Panagiotou
authors: First Department of Intensive Care Medicine, Evaggelismos Hospital, University of Athens Medical School, Athens, Greece.
authors: Anna
authors: A
authors: Panagiotou
authors: Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors: Ioannis
authors: I
authors: Morianos
authors: First Department of Intensive Care Medicine, Evaggelismos Hospital, University of Athens Medical School, Athens, Greece.
authors: Eleni
authors: E
authors: Litsiou
authors: Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
authors: Aikaterini I
authors: AI
authors: Trochoutsou
authors: Thoracic Surgery, Sotiria Chest Hospital, Athens, Greece.
authors: Maria
authors: M
authors: Konstantinou
authors: Thoracic Surgery, Sotiria Chest Hospital, Athens, Greece.
authors: Konstantinos
authors: K
authors: Potaris
authors: Airway Disease Infection Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors: Joseph
authors: J
authors: Footitt
authors: Airway Disease Infection Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors: Patrick
authors: P
authors: Mallia
authors: First Department of Intensive Care Medicine, Evaggelismos Hospital, University of Athens Medical School, Athens, Greece.
authors: Spyros
authors: S
authors: Zakynthinos
authors: Airway Disease Infection Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors: Sebastian L
authors: SL
authors: Johnston
authors: Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece. Electronic address: gxanthou@bioacademy.gr.
authors: Georgina
authors: G
authors: Xanthou
mesh_terms: D000368:Aged; D018949:Antigens, CD1 / Q000378:metabolism; D024201:Bystander Effect; D002454:Cell Differentiation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D018450:Disease Progression; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D060889:Inducible T-Cell Co-Stimulator Protein / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D064094:Interleukin-27 / Q000235:genetics / Q000378:metabolism*; D007519:Isoantigens / Q000276:immunology; D008168:Lung / Q000276:immunology*; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000276:immunology* / Q000821:virology; D012229:Rhinovirus / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D018949:Antigens, CD1; C437944:CD1C protein, human; D006023:Glycoproteins; D060889:Inducible T-Cell Co-Stimulator Protein; D064094:Interleukin-27; D007519:Isoantigens; D016753:Interleukin-10
keywords: Chronic obstructive pulmonary disease; IL-10; IL-27; dendritic cells; inducible costimulator ligand; regulatory T cells