Interferon regulatory factor 5 (IRF5) is a key transcription factor involved in the control of the
expression of pro-inflammatory cytokine and responses to infection, however its role in regulating
pulmonary immune responses to allergen is unknown. We used genetic ablation, adenoviral
vector-driven overexpression and adoptive transfer approaches to interrogate the role of IRF5 in
pulmonary immunity and during challenge with the aero-allergen, house dust mite. Global IRF5
deficiency resulted in impaired lung function and extracellular matrix (ECM) deposition. IRF5
was also essential for effective responses to inhaled allergen, controlling airway hyper-
responsiveness, mucus secretion and eosinophilic inflammation. Adoptive transfer of IRF5-
deficient alveolar macrophages into the WT pulmonary milieu was sufficient to drive airway
hyper-reactivity, at baseline or following antigen challenge. These data identify IRF5-expressing
macrophages as a key component of the immune defence of the airways. Manipulation of IRF5
activity in the lung could therefore be a viable strategy for the redirection of pulmonary immune
responses and thus, the treatment of lung disorders.