The broad, long-term objective of this application is to define the role of gamma delta T cells in the regulation of airway functions. This process is of vital importance during pulmonary infection, exposure to environmental pollutants, and allergic exposure in sensitized hosts, but the underlying mechanisms that maintain it are still poorly understood. The investigators have found that murine gamma delta T cells regulate airway tone during innate and allergic immune responses to the model allergen chicken ovalbumin (cOVA). They propose to characterize this newly discovered function of gamma delta T cells, to define how this process activates gamma delta T cells, and to investigate the mechanism of gamma delta T cell-dependent airway regulation. They hypothesize that cOVA is specifically recognized by airway phagocytes and endocytosed, which stimulates an innate response that in turn activates gamma delta T cells. Activated gamma delta T cells then modulate the innate response via a negative feedback mechanism, and thereby control the effect of this response of airway function, particularly airway tone. To test this, they will: 1. Determine which gamma delta T cells are responsible for the regulation of innate airway responses initiated by inhalation of nebulized cOVA. They will further document the critical role of local, pulmonary populations and identify TCR-defined subsets regulating airway tone. 2. Define how cOVA induces innate airway responses, including the initiation of gamma delta T cell regulatory function. 3. Identify the targets of gamma delta T cell regulation in the innate airway response to cOVA. They will delineate the targets of gamma delta T cell regulation, including the innate endocytic response of airway phagocytes, airway cytokine production, and airway epithelial cell function. 4. Compare gamma delta T cell regulatory functions in the innate airway response and in allergic airway hyper-responsiveness induced by cOVA. Two basic ideas will be tested, namely that gamma delta T cells functions are the same regardless of the mechanism of airway stimulation, and secondly, that gamma delta T cells specifically control antigen-specific alpha beta T cells during allergic airway hyper-responsiveness.
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