Thursday, July 16, 2015
Grand Hall and Gallery, Ground Floor & 1st Floor (Maritim Hotel)
Heleen Vroman, MSc
,
Pulmonary Medicine, Erasmus MC, Rotterdam, Netherlands
Ingrid M. Bergen, BASc
,
Pulmonary Medicine, Erasmus MC, Rotterdam, Netherlands
Björn E. Clausen, Prof, PhD
,
University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
Bart N. Lambrecht, Prof, PhD, MD
,
Pulmonary Medicine, Erasmus MC, Rotterdam, Netherlands
Rudi W. Hendriks, Prof, PhD
,
Pulmonary Medicine, Erasmus MC, Rotterdam, Netherlands
Bernt van den Blink, MD, PhD
,
Pulmonary Medicine, Erasmus MC, Rotterdam, Netherlands
Mirjam Kool, PhD
,
Pulmonary Medicine, Erasmus MC, Rotterdam, Netherlands
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.
A20fl/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-A20WT mice displayed an asthmatic phenotype in broncho-alveolar lavage, with increased eosinophils, and Th2 cells/cytokines. Surprisingly, asthmatic characteristics were reduced in langerin-A20KO mice, while Tregs and IL-10+ CD8 T cell numbers were increased compared to langerin-A20WT mice. Co-culturing OT-II cells with sorted CD103+cDCs from Langerin-A20KO mice specifically induced a increased proliferation of Tregs, compared to CD103+cDCs from Langerin-A20WT mice. Lung CD103+cDCs of Langerin-A20KOmice 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.