Natural killer cell NKG2D and granzyme B are critical for allergic pulmonary inflammation

• Published in: Journal of allergy and clinical immunology Vol. 133; no. 3; pp. 827 - 835.e3
• Main Authors: Farhadi, Nazanin, MSc, Lambert, Laura, BA, Triulzi, Chiara, PhD, Openshaw, Peter J.M., FMedSci, Guerra, Nadia, PhD, Culley, Fiona J., PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.03.2014; Elsevier; Elsevier Limited; Mosby
• Subjects: allergic inflammation; Allergies; Allergy and Immunology; Animals; asthma; Asthma - etiology; Asthma - immunology; Biological and medical sciences; Chronic obstructive pulmonary disease, asthma; Cytokines; Dermatophagoides pteronyssinus; Female; Flow cytometry; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Granzymes - physiology; house dust mite; Immune system; Immunopathology; Infections; Innate immunity; Killer Cells, Natural - immunology; Ligands; lung; Lung diseases; Lymphocytes; Mechanisms of Allergy and Clinical Immunology; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mortality; natural killer cell; NK Cell Lectin-Like Receptor Subfamily K - physiology; Pneumology; Pneumonia - etiology; Pneumonia - immunology; Pyroglyphidae - immunology; Rodents; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; T cell receptors; Viral infections; United Kingdom > UK; allergic inflammation; house dust mite; KO; Innate immunity; asthma; Wild type; BAL; lung; HDM; Respiratory syncytial virus; APC; RSV; Bronchoalveolar lavage; Natural killer; Allophycocyanin; natural killer cell; NK; WT; Knock-out; Lung disease; Allergy; Immunopathology; Serine endopeptidases; Enzyme; Respiratory disease; NKG2D receptor; Lung; House dust; Mite; Natural immunity; Inflammation; Respiratory system; Asthma; Natural killer cell; Peptidases; Granzyme B; Immunology; Hydrolases; Bronchus disease; Obstructive pulmonary disease
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2013.09.048

Background The diverse roles of innate immune cells in the pathogenesis of asthma remain to be fully defined. Natural killer (NK) cells are innate lymphocytes that can regulate adaptive immune responses. NK cells are activated in asthma; however, their role in allergic airway inflammation is not fully understood. Objective We investigated the importance of NK cells in house dust mite (HDM)-triggered allergic pulmonary inflammation. Specifically, we aimed to determine the role of the major NK-cell activating receptor NKG2D and NK-cell effector functions mediated by granzyme B. Methods Allergic airway inflammation was induced in the airways of mice by repeated intranasal HDM extract administration and responses in wild-type and NKG2D-deficient mice were compared. Adoptive transfer studies were used to identify the cells and mechanisms involved. Results Mice that lacked NKG2D were resistant to the induction of allergic inflammation and showed little pulmonary eosinophilia, few airway TH 2 cells, and no rise in serum IgE after multiple HDM-allergen exposures. However, NKG2D was not required for pulmonary inflammation after a single inoculation of allergen. NKG2D-deficient mice showed no alteration in responses to respiratory virus infection. Transfer of wild-type NK cells (but not CD3+ cells) into NKG2D-deficient mice restored allergic inflammatory responses only if the NK cells expressed granzyme B. Conclusions These studies established a pivotal role for NK-cell NKG2D and granzyme B in the pathogenesis of HDM-induced allergic lung disease, and identified novel therapeutic targets for the prevention and treatment of asthma.