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 which 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 lacking NKG2D were resistant to the induction of allergic inflammation and showed little pulmonary eosinophilia, few airway Th2 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.

Conclusion
These studies establish a pivotal role for NK cell NKG2D and granzyme B in the pathogenesis of HDM induced allergic lung disease, and identify novel therapeutic targets for the prevention and treatment of asthma.