Sublingual allergen immunotherapy (SLIT) prevents house dust mite inhalant type 2 immunity through DC-mediated induction of Foxp3+ regulatory T cells

Sublingual allergen immunotherapy (SLIT) is an emerging treatment option for allergic asthma, and a potential disease modifying strategy for asthma prevention. The key cellular events leading to such long term tolerance remains to be fully elucidated. We administered prophylactic SLIT in a mouse model of house dust mite (HDM) driven allergic asthma. HDM extract was sublingually administered over 3 weeks followed by intratracheal sensitization and intranasal challenges with HDM. Prophylactic SLIT prevented allergic airway inflammation and hyperreactivity with a low lab-to-lab variation. The HDM specific Th2 (CD4 T helper) response was shifted by SLIT towards a regulatory and Th17 response in lung and mediastinal lymph node (MLN). By using Der p 1 specific CD4+ T cells (1-DER), we found that SLIT blocked 1-DER T cell recruitment to the MLN and dampened IL-4 secretion following intratracheal HDM sensitization. Sublingually administered Der p 1 protein activated 1-DER T cells in the cervical lymph node (CLN) via CCR7+ migratory dendritic cells (DC). DCs migrating from the oral submucosa to the CLN after SLIT induced Foxp3+ regulatory T cells. When mice were sensitized with HDM, prior prophylactic SLIT increased Der p 1 specific Tregs and lowered Th2 recruitment in the lung. By using Foxp3-DTR mice, Tregs were found to contribute to the immunoregulatory prophylactic effect of SLIT on type 2 immunity. These findings in a mouse model suggest that DC-mediated functional Treg induction in oral mucosa draining LNs is one of the driving mechanisms behind the disease modifying effect of prophylactic SLIT.