Inhaled allergen‐driven CD1c up‐regulation and enhanced antigen uptake by activated human respiratory‐tract dendritic cells in atopic asthma

Abstract

Background Dendritic cells (DC) mediate inflammation in rodent models of allergic airway disease, but the role played by human respiratory-tract DC (hRTDC) in atopic asthma remains poorly defined. Recent data suggest that CD1 antigen presentation by hRTDC may contribute to asthma pathogenesis. Objective To investigate the influence of hRTDC on the balance between atopy and allergic asthma in human subjects and to determine whether CD1 expression by hRTDC is modulated during asthmatic inflammation. Methods Sputum cells were induced from steroid-naïve, allergen-challenged and allergennaïve subjects (atopic asthmatics, atopic non-asthmatics and non-atopic controls). hRTDC were identified using monoclonal antibody labelling and analysis by flow cytometry. Results hRTDC stained HLA-DR 1 (negative for markers of other cell lineages) were predominantly myeloid and comprised $0.5% of viable sputum cells. Sputum cells were potent stimulators of allogeneic CD4 1 naïve T cells and enrichment/depletion experiments correlated stimulatory potency with DC numbers. Sputum contained cells that exhibited typical dendritic morphology when analysed by electron microscopy. Myeloid hRTDC were endocytically active, but uptake of FITC-dextran was enhanced in cells from asthmatics (P o 0.001). Despite their increased endocytic capacity, asthmatic myeloid hRTDC appeared mature and expressed increased levels of maturation markers (P o 0.05-P o 0.001), CD1c, CD1d and langerin (P o 0.05). CD1c expression by asthmatic myeloid hRTDC was enhanced upon in vivo allergen challenge (three to ninefold within 24 h; P o 0.05). CD11c À CD123 high hRTDC were only detected in asthmatic sputum and were increased in number following allergen challenge. Conclusion Despite limited cell numbers, it proved possible to analyse human RTDC in induced sputum, providing evidence that increased antigen uptake and enhanced CD1 presentation by activated hRTDC may contribute to allergic airway disease. CD1 presentation by hRTDC in atopic asthma may therefore constitute a novel target for future intervention strategies.

Airway Epithelial Cells Regulate the Functional Phenotype of Locally Differentiating Dendritic Cells: Implications for the Pathogenesis of Infectious and Allergic Airway Disease

“…3), a function that has been shown to be inversely correlated with the maturational status of DCs (51). This dichotomy of phenotype and function has been recently documented in an in vivo study of respiratory tract DCs from human subjects which showed that whereas DC from atopic asthmatic airways displayed higher levels of maturation markers, they were more adept at endocytosis than healthy controls (53). Their data and ours collectively suggest that regulation of phenotypic maturation and Ag uptake can be uncoupled in the airways and that AEC may play a role in the differential regulation of the two processes.…”

Allergen-induced airway responses

“…There is a possible role of mDC2s in allergic asthma. Studies have demonstrated that, while all three DC subpopulations are present in asthmatic lungs [80], BAL fluid [81] and in induced sputum [82], mDC2s are more frequent than mDC1s and pDCs [80]. Allergen exposure upregulates thrombomodulin in mDCs and mDC2s induce a greater type-2 cytokine response by allergen-specific T-cells [78].…”

Myeloid and plasmacytoid dendritic cells in induced sputum after allergen inhalation in subjects with asthma

“…Previous research in peripheral blood has suggested that DCs migrate from circulation during the allergen-induced asthmatic response [13][14][15] ; however, a comprehensive study investigating DCs in the airways after allergen inhalation has yet to be conducted. Airway DCs have been identified in asthmatic airway biopsies 16 and in a small number of subjects with allergic asthma in induced sputum 17 ; however, the temporal association of allergen-induced airway inflammation and airway mDCs and pDCs has not been examined. Accordingly, we examined the kinetics of DCs in the sputum of subjects with allergic asthma after inhalation of allergen.…”