Fibrinogen-cleavage products and TLR4 promote the generation of programmed cell death 1 ligand 2(PD-L2)+ dendritic cells in allergic asthma

Journal of Allergy and Clinical Immunology

4 years ago

Fibrinogen-cleavage products and TLR4 promote the generation of programmed cell death 1 ligand 2(PD-L2)+ dendritic cells in allergic asthma

Inhaled protease allergens preferentially trigger Th2-mediated inflammation in allergic asthma. The role of dendritic cells (DCs) on the induction of Th2 cell responses in allergic asthma has been well documented; however, the mechanism by which protease allergens induce Th2-favorable DCs in the airway remains unclear.

Objective

We sought to determine a subset of DCs responsible for Th2 cell responses in allergic asthma and the mechanism by which protease allergens induce the DC subset in the airway.

Methods

Mice were intranasally challenged with protease allergens or fibrinogen-cleavage product (FCP) to induce allergic airway inflammation. DCs isolated from the 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 TLR4-deficient mice were used for further mechanistic studies.

Results

Protease allergens induced a remarkable accumulation of Th2-favorable PD-L2⁺ DCs in the mediastinal lymph nodes, which was significantly abolished in mice depleted of mast cells and, to a lesser extent, innate lymphoid cells. Mechanistically, FCP generated by protease allergens triggered IL-13 production from wild-type mast cells but not from TLR4-deficient mast cells, which resulted in the increase of PD-L2⁺ DCs. Intranasal administration of FCP induced an increase of PD-L2⁺ DCs in the airway, which was significantly abolished in TLR4- and mast cell-deficient mice. Injection of IL-13 restored 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 the generation of Th2-favorable PD-L2⁺ DCs in allergic asthma, and suggest that targeting PD-L2⁺ DC pathway might be effective in suppressing allergic T cell responses in the airway.

Publisher URL: www.sciencedirect.com/science

DOI: S0091674917315828