Abstract
BACKGROUND: Asthma is defined as a chronic inflammatory disease of the airways; however, the underlying physiologic and immunologic processes are not fully understood. OBJECTIVE: The aim of this study was to determine whether TH9 cells develop in vivo in a model of chronic airway hyperreactivity (AHR) and what factors control this development. METHOD: We have developed a novel chronic allergen exposure model using the clinically relevant antigen Aspergillus fumigatus to determine the time kinetics of TH9 development in vivo. RESULTS: TH9 cells were detectable in the lungs after chronic allergen exposure. The number of TH9 cells directly correlated with the severity of AHR, and anti-IL-9 treatment decreased airway inflammation. Moreover, we have identified programmed cell death ligand (PD-L) 2 as a negative regulator of TH9 cell differentiation. Lack of PD-L2 was associated with significantly increased TGF-β and IL-1α levels in the lungs, enhanced pulmonary TH9 differentiation, and higher morbidity in the sensitized mice. CONCLUSION: Our findings suggest that PD-L2 plays a pivotal role in the regulation of TH9 cell development in chronic AHR, providing novel strategies for modulating adaptive immunity during chronic allergic responses.