title: NKG2D mediates NK cell hyperresponsiveness and influenza-induced pathologies in a mouse model of chronic obstructive pulmonary disease.
abstract: Chronic obstructive pulmonary disease (COPD) is characterized by peribronchial and perivascular inflammation and largely irreversible airflow obstruction. Acute disease exacerbations, due frequently to viral infections, lead to enhanced disease symptoms and contribute to long-term progression of COPD pathology. Previously, we demonstrated that NK cells from cigarette smoke (CS)-exposed mice exhibit enhanced effector functions in response to stimulating cytokines or TLR ligands. In this article, we show that the activating receptor NKG2D is a key mediator for CS-stimulated NK cell hyperresponsiveness, because CS-exposed NKG2D-deficient mice (Klrk1(-/-)) did not exhibit enhanced effector functions as assessed by cytokine responsiveness. NK cell cytotoxicity against MHC class I-deficient targets was not affected in a COPD model. However, NK cells from CS-exposed mice exhibit greater cytotoxic activity toward cells that express the NKG2D ligand RAET1ε. We also demonstrate that NKG2D-deficient mice exhibit diminished airway damage and reduced inflammation in a model of viral COPD exacerbation, which do not affect viral clearance. Furthermore, adoptive transfer of NKG2D(+) NK cells into CS-exposed, influenza-infected NKG2D-deficient mice recapitulated the phenotypes observed in CS-exposed, influenza-infected wild-type mice. Our findings indicate that NKG2D stimulation during long-term CS exposure is a central pathway in the development of NK cell hyperresponsiveness and influenza-mediated exacerbations of COPD.
authors.affiliation: Division of Environmental Genetics and Molecular Toxicology, Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Wortham
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Eppert
authors.forename: Greg T
authors.initials: GT
authors.lastname: Motz
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Flury
authors.forename: Mauricio
authors.initials: M
authors.lastname: Orozco-Levi
authors.forename: Kasper
authors.initials: K
authors.lastname: Hoebe
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: Panos
authors.forename: Melissa
authors.initials: M
authors.lastname: Maxfield
authors.forename: Stephan W
authors.initials: SW
authors.lastname: Glasser
authors.forename: Albert P
authors.initials: AP
authors.lastname: Senft
authors.forename: David H
authors.initials: DH
authors.lastname: Raulet
authors.forename: Michael T
authors.initials: MT
authors.lastname: Borchers
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D006801:Humans; D053122:Influenza A Virus, H3N2 Subtype / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000276:immunology*; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D015395:Histocompatibility Antigens Class I; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D014028:Tobacco Smoke Pollution