Activation of lung CD103+ conventional DCs reduces allergen driven asthma

Asthma is a Th2-mediated inflammatory lung disorder in response to inhaled antigens, such as house dust mite (HDM). Dendritic cells (DCs) are crucial for both induction (CD11b⁺cDCs) and maintenance of asthmatic immune responses (moDCs), whereas pDCs and CD103⁺cDCs are described to be tolerogonic. DCs can be activated upon TLR stimulation, initiating the NF-κB pathway, which is negatively regulated by A20. Absence of A20 in DCs leads to their overt activation. In this study, we investigated whether activation of CD103⁺cDCs further increases their tolerogenic function in asthma.

                A20^fl/flxLangerin-cre (Langerin-A20 mice) mice were exposed to a HDM-driven model for asthma. Sorted DC subsets from MLN of Langerin-A20 mice were also co-cultured with OT-II cells to determine DC specific Th cell differentiation and proliferation.

                HDM-sensitized langerin-A20^WT mice displayed an asthmatic phenotype in broncho-alveolar lavage, with increased eosinophils, and Th2 cells/cytokines. Surprisingly, asthmatic characteristics were reduced in langerin-A20^KO mice, while Tregs and IL-10⁺ CD8 T cell numbers were increased compared to langerin-A20^WT mice. Co-culturing OT-II cells with sorted CD103⁺cDCs from Langerin-A20^KO mice specifically induced a increased proliferation of Tregs, compared to CD103⁺cDCs from Langerin-A20^WT mice. Lung CD103⁺cDCs of Langerin-A20^KOmice showed increased PD-L1 expression, while no differences were observed in ICOSL, IL-10 and TGF-β.

                Activated CD103⁺cDCs dampen asthmatic inflammation through induction of Tregs and tolerogenic CD8⁺ T cells, probably mediated by increased PD-L1 expression. These results offer new insights in the pathogenesis of asthma, and could contribute to new potential strategies to treat asthma patients.