Fibrinogen cleavage products and Toll-like receptor 4 promote the generation of programmed cell death 1 ligand 2-positive dendritic cells in allergic asthma.

BACKGROUND

Inhaled protease allergens preferentially trigger T2-mediated inflammation in allergic asthma. The role of dendritic cells (DCs) on induction of T2 cell responses in allergic asthma has been well documented; however, the mechanism by which protease allergens induce T2-favorable DCs in the airway remains unclear.

OBJECTIVE

We sought to determine a subset of DCs responsible for T2 cell responses in allergic asthma and the mechanism by which protease allergens induce the DC subset in the airway.

METHODS

Mice were challenged intranasally with protease allergens or fibrinogen cleavage products (FCPs) to induce allergic airway inflammation. DCs isolated from mediastinal lymph nodes were analyzed for surface phenotype and T-cell stimulatory function. Anti-Thy1.2 and Mas-TRECK mice were used to deplete innate lymphoid cells and mast cells, respectively. Adoptive cell transfer, bone marrow DC culture, anti-IL-13, and Toll-like receptor (TLR) 4-deficient mice were used for further mechanistic studies.

RESULTS

Protease allergens induced a remarkable accumulation of T2-favorable programmed cell death 1 ligand 2 (PD-L2) DCs in mediastinal lymph nodes, which was significantly abolished in mice depleted of mast cells and, to a lesser extent, innate lymphoid cells. Mechanistically, FCPs generated by protease allergens triggered IL-13 production from wild-type mast cells but not from TLR4-deficient mast cells, which resulted in an increase in the number of PD-L2 DCs. Intranasal administration of FCPs induced an increase in numbers of PD-L2 DCs in the airway, which was significantly abolished in TLR4- and mast cell-deficient mice. Injection of IL-13 restored the PD-L2 DC population in mice lacking mast cells.

CONCLUSION

Our findings unveil the "protease-FCP-TLR4-mast cell-IL-13" axis as a molecular mechanism for generation of T2-favorable PD-L2 DCs in allergic asthma and suggest that targeting the PD-L2 DC pathway might be effective in suppressing allergic T-cell responses in the airway.