title: Sustained CTL activation by murine pulmonary epithelial cells promotes the development of COPD-like disease.
abstract: Chronic obstructive pulmonary disease (COPD) is a lethal progressive lung disease culminating in permanent airway obstruction and alveolar enlargement. Previous studies suggest CTL involvement in COPD progression; however, their precise role remains unknown. Here, we investigated whether the CTL activation receptor NK cell group 2D (NKG2D) contributes to the development of COPD. Using primary murine lung epithelium isolated from mice chronically exposed to cigarette smoke and cultured epithelial cells exposed to cigarette smoke extract in vitro, we demonstrated induced expression of the NKG2D ligand retinoic acid early transcript 1 (RAET1) as well as NKG2D-mediated cytotoxicity. Furthermore, a genetic model of inducible RAET1 expression on mouse pulmonary epithelial cells yielded a severe emphysematous phenotype characterized by epithelial apoptosis and increased CTL activation, which was reversed by blocking NKG2D activation. We also assessed whether NKG2D ligand expression corresponded with pulmonary disease in human patients by staining airway and peripheral lung tissues from never smokers, smokers with normal lung function, and current and former smokers with COPD. NKG2D ligand expression was independent of NKG2D receptor expression in COPD patients, demonstrating that ligand expression is the limiting factor in CTL activation. These results demonstrate that aberrant, persistent NKG2D ligand expression in the pulmonary epithelium contributes to the development of COPD pathologies.
authors.affiliation: Department of Environmental Health, Division of Environmental Genetics, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0056, USA. michael.borchers@uc.edu
authors.forename: Michael T
authors.initials: MT
authors.lastname: Borchers
authors.forename: Scott C
authors.initials: SC
authors.lastname: Wesselkamper
authors.forename: Victor
authors.initials: V
authors.lastname: Curull
authors.forename: Alba
authors.initials: A
authors.lastname: Ramirez-Sarmiento
authors.forename: Albert
authors.initials: A
authors.lastname: Sánchez-Font
authors.forename: Judith
authors.initials: J
authors.lastname: Garcia-Aymerich
authors.forename: Carlos
authors.initials: C
authors.lastname: Coronell
authors.forename: Josep
authors.initials: J
authors.lastname: Lloreta
authors.forename: Alvar G
authors.initials: AG
authors.lastname: Agusti
authors.forename: Joaquim
authors.initials: J
authors.lastname: Gea
authors.forename: John A
authors.initials: JA
authors.lastname: Howington
authors.forename: Michael F
authors.initials: MF
authors.lastname: Reed
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Starnes
authors.forename: Nathaniel L
authors.initials: NL
authors.lastname: Harris
authors.forename: Mark
authors.initials: M
authors.lastname: Vitucci
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Eppert
authors.forename: Gregory T
authors.initials: GT
authors.lastname: Motz
authors.forename: Kevin
authors.initials: K
authors.lastname: Fogel
authors.forename: Dennis W
authors.initials: DW
authors.lastname: McGraw
authors.forename: Jay W
authors.initials: JW
authors.lastname: Tichelaar
authors.forename: Mauricio
authors.initials: M
authors.lastname: Orozco-Levi
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D004646:Emphysema / Q000209:etiology / Q000276:immunology; D005786:Gene Expression Regulation; D007694:Killer Cells, Natural / Q000276:immunology; D008168:Lung / Q000503:physiopathology*; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000276:immunology* / Q000503:physiopathology; D020545:Respiratory Mucosa / Q000503:physiopathology*; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects*
chemical_list: C527086:Klrk1 protein, mouse; D008565:Membrane Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; C491219:Raet1a protein, mouse; D012906:Smoke