Sustained CTL activation by murine pulmonary epithelial cells promotes the development of COPD-like disease. J Clin Invest 2009 Mar;119(3):636-49
Date
02/07/2009Pubmed ID
19197141Pubmed Central ID
PMC2648699DOI
10.1172/JCI34462Scopus ID
2-s2.0-65649102628 (requires institutional sign-in at Scopus site) 62 CitationsAbstract
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.
Author List
Borchers MT, Wesselkamper SC, Curull V, Ramirez-Sarmiento A, Sánchez-Font A, Garcia-Aymerich J, Coronell C, Lloreta J, Agusti AG, Gea J, Howington JA, Reed MF, Starnes SL, Harris NL, Vitucci M, Eppert BL, Motz GT, Fogel K, McGraw DW, Tichelaar JW, Orozco-Levi MMESH terms used to index this publication - Major topics in bold
AnimalsCD8-Positive T-Lymphocytes
Disease Models, Animal
Emphysema
Gene Expression Regulation
Killer Cells, Natural
Lung
Lymphocyte Activation
Membrane Proteins
Mice
NK Cell Lectin-Like Receptor Subfamily K
Pulmonary Disease, Chronic Obstructive
Respiratory Mucosa
Smoke
Smoking
