Ly6G+Nur77+ perivascular macrophages initiate type-2 immune responses to allergens in the lung

The mechanisms of allergen sensing and type 2 immune response initiation remain unclear. Using a house dust mite (HDM)-induced allergic airway model, we demonstrated that host detection of protease activity in HDM was crucial for initiating T helper type 2 (Th2) responses. This process was driven by the major allergen Der p 1, a cysteine protease, which was sensed by protease-activated receptor 2 (PAR2) on a novel population of perivascular lung macrophages expressing Ly6G and nuclear receptor Nur77. These macrophages required PAR2 and Nur77 for activation and accumulation and regulated conventional dendritic cell (mDC) migration to draining mediastinal lymph nodes (mLN) via cysteinyl leukotriene (CysLTs) production. CysLTs enhanced CCR7-driven migration of mDCs toward its ligand, CCL21, facilitating arrival to mLNs for T cell priming and expansion. Inhibiting CysLTs biosynthesis reduced mDC migration and dampened Th2 allergic responses, highlighting new therapeutic paths and mechanisms in type 2 immunity.