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* Department of Environmental Health, Division of Environmental Genetics and Molecular Toxicology, University of Cincinnati College of Medicine, Cincinnati, OH 45267;
Department of Pathobiology, University of Illinois-Champaign College of Veterinary Medicine, Urbana, IL 61802;
Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267; and
Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati College of Medicine, University of Cincinnati, Cincinnati, OH 45267
Pseudomonas aeruginosa is a major cause of nosocomial respiratory infections. The eradication of P. aeruginosa from the lung involves the orchestrated actions of the pulmonary epithelium and both resident and recruited immune cells. The NKG2D receptor is constitutively expressed on the surface of circulating and tissue-resident NK cells (and other cytotoxic lymphocytes), and is capable of controlling NK cell activation and production of cytokines, such as IFN-
via interactions with ligands expressed on the surface of stressed cells. Previously, we demonstrated that NKG2D mediates pulmonary clearance of P. aeruginosa. In the present study, we investigated the cellular and molecular mechanisms of NKG2D-mediated clearance of P. aeruginosa using a novel transgenic mouse model of doxycycline-inducible conditional expression of NKG2D ligands (retinoic acid early transcript 1, 
) in pulmonary epithelial cells. NKG2D ligand expression in this model increased pulmonary clearance, cellular phagocytosis, and survival following P. aeruginosa respiratory infection. Additionally, NK cell sensitivity to ex vivo LPS stimulation was greater in lung cells isolated from naive transgenic mice administered doxycycline. We also showed that NK cells are the primary source of lymphocyte-derived IFN- in response to P. aeruginosa respiratory infection. Significantly, we demonstrated that NKG2D is critical to the nonredundant IFN- production by pulmonary NK cells following acute P. aeruginosa infection. These results represent the principal report of NKG2D-mediated activation of lung NK cells following respiratory infection with an opportunistic pathogen and further establish the importance of NKG2D in the host response against P. aeruginosa respiratory infection.
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1 This work was supported by National Institutes of Health Grant ES015036 (to M.T.B.) and a Pilot Project Grant (to S.C.W.) within the University of Cincinnati, Department of Environmental Health’s Center for Environmental Genetics ES006096.
2 Address correspondence and reprint requests to Dr. Michael T. Borchers, Department of Environmental Health, P.O. Box 670056, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0056. E-mail address: michael.borchers{at}uc.edu
3 Abbreviations used in this paper: CF, cystic fibrosis; BAL, bronchoalveolar lavage; DOX, doxycycline; Raetl, retinoic acid early transcript; TTSS, type III secretion system.
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