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

Publication date: Available online 14 October 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Minkyoung Cho, Jeong-Eun Lee, Hoyong Lim, Hyun-Woo Shin, Roza Khalmuratova, Garam Choi, Hyuk Soon Kim, Wahn Soo Choi, Young-Jun Park, Inbo Shim, Byung-Seok Kim, Chang-Yuil Kang, Jae-Ouk Kim, Shinya Tanaka, Masato Kubo, Yeonseok Chung
BackgroundInhaled 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.ObjectiveWe 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.MethodsMice 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.ResultsProtease 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.ConclusionOur 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.

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