The NKG2D-activating receptor is expressed on cytotoxic lymphocytes and interacts with
ligands expressed on the surface of cells stressed by pathogenic and nonpathogenic stimuli. In this study, we investigated the physiologic importance of
NKG2D receptor-
ligand interactions in response to acute pulmonary
Pseudomonas aeruginosa infection. P. aeruginosa
infection increased the expression of mouse NKG2D
ligands (Rae1) in airway epithelial cells and alveolar macrophages in vivo and also increased the cell surface expression of human NKG2D
ligands (ULBP2) on airway epithelial cells in vitro.
NKG2D receptor blockade with a specific
monoclonal antibody inhibited the pulmonary clearance of P. aeruginosa.
NKG2D receptor blockade also resulted in decreased production of Th1
cytokines and
nitric oxide in the lungs of P. aeruginosa-infected mice. Additionally,
NKG2D receptor blockade reduced the epithelial cell sloughing that accompanies P. aeruginosa
infection. Macrophage phagocytosis and bronchoalveolar lavage cellularity were not different in P. aeruginosa-infected mice with and without
NKG2D receptor blockade. These results demonstrate the importance of NKG2D-mediated immune activation in the clearance of acute
bacterial infection and suggest that epithelial cell-lymphocyte interactions mediate pulmonary
cytokine production, epithelial cell integrity, and bacterial clearance.