Tolerogenic signaling by pulmonary CD1c+ dendritic cells induces regulatory T cells in patients with chronic obstructive pulmonary disease by IL-27/IL-10/inducible costimulator ligand

Tsoumakidou, Maria; Tousa, Sofia; Semitekolou, Maria; Panagiotou, Panagiota; Panagiotou, Anna; Morianos, Ioannis; Litsiou, Eleni; Trochoutsou, Aikaterini; Konstantinou, Maria; Potaris, Konstantinos; Footitt, Joseph; Mallia, Patrick; Zakynthinos, Spyros; Johnston, Sebastian L.; Xanthou, Georgina

doi:10.1016/j.jaci.2014.05.045

Cited by 38 publications

(39 citation statements)

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“…Further analyses of differentially expressed genes on these subpopulations would be valuable to convincingly determine their ontogeny. Our identification of CD1c + MDCs, CD141 + MDCs, and PDCs in lung tissue and airway lumen is in line with previous studies using lung tissue (14,22,24,26,36) and BAL (23,25,29,31,33) in both healthy and diseased conditions. In this study, in addition to identifying specific DC subsets, we have mapped the anatomical distribution of DCs at steady-state in the lungs in the same subjects.…”

Section: Discussionsupporting

confidence: 91%

“…In studies applying more advanced flow cytometry panels, noncancerous lung tissue from surgical resections of patients were typically used (14,(26)(27)(28), although it is unclear whether these rare populations are truly representative of DCs present in healthy subjects. Indeed, several studies have investigated DCs in the context of lung diseases such as asthma, chronic obstructive pulmonary disease, bronchiolitis, and sarcoidosis (29)(30)(31)(32)(33)(34)(35). In chronic obstructive pulmonary disease, the expression of maturation molecules on DCs has been proposed as a potential diagnostic/therapeutic target.…”

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confidence: 99%

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Dendritic Cells and Monocytes with Distinct Inflammatory Responses Reside in Lung Mucosa of Healthy Humans

Baharom

Schlüter

Rankin

et al. 2016

The Journal of Immunology

109

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Every breath we take contains potentially harmful pathogens or allergens. Dendritic cells (DCs), monocytes, and macrophages are essential in maintaining a delicate balance of initiating immunity without causing collateral damage to the lungs because of an exaggerated inflammatory response. To document the diversity of lung mononuclear phagocytes at steady-state, we performed bronchoscopies on 20 healthy subjects, sampling the proximal and distal airways (bronchial wash and bronchoalveolar lavage, respectively), as well as mucosal tissue (endobronchial biopsies). In addition to a substantial population of alveolar macrophages, we identified subpopulations of monocytes, myeloid DCs (MDCs), and plasmacytoid DCs in the lung mucosa. Intermediate monocytes and MDCs were highly frequent in the airways compared with peripheral blood. Strikingly, the density of mononuclear phagocytes increased upon descending the airways. Monocytes from blood and airways produced 10-fold more proinflammatory cytokines than MDCs upon ex vivo stimulation. However, airway monocytes were less inflammatory than blood monocytes, suggesting a more tolerant nature. The findings of this study establish how to identify human lung mononuclear phagocytes and how they function in normal conditions, so that dysregulations in patients with respiratory diseases can be detected to elucidate their contribution to immunity or pathogenesis.

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Section: Discussionsupporting

confidence: 91%

mentioning

confidence: 99%

Dendritic Cells and Monocytes with Distinct Inflammatory Responses Reside in Lung Mucosa of Healthy Humans

Baharom

Schlüter

Rankin

et al. 2016

The Journal of Immunology

109

View full text Add to dashboard Cite

show abstract

“…Through upregulation of PD-L1, IFN-g leads to induction of tolerogenic properties in DCs (43,58), which acquire the capability to effectively suppress T cell responses in a PD-L1/PD-1-dependent manner (42,62,63). Furthermore, the ability of IL-27 as an inducer of tolerogenic DCs was recently confirmed in a clinical study in chronic obstructive pulmonary disease that provided evidence that IL-27-exposed DCs induced regulatory T cells in obstructive pulmonary disease patients (64). Taken together and in concordance with the current literature, our data suggest that IL-27 is the central cytokine mediating the antiallergic effect of R848 in our model.…”

Section: Discussionmentioning

confidence: 88%

IL-27 Is Essential for Suppression of Experimental Allergic Asthma by the TLR7/8 Agonist R848 (Resiquimod)

Jirmo

Daluege

Happle

et al. 2016

The Journal of Immunology

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Different models of experimental allergic asthma have shown that the TLR7/8 agonist resiquimod (R848) is a potential inhibitor of type 2 helper cell–driven inflammatory responses. However, the mechanisms mediating its therapeutic effects are not fully understood. Using a model of experimental allergic asthma, we show that induction of IL-27 by R848 is critical for the observed ameliorative effects. R848 significantly inhibited all hallmarks of experimental allergic asthma, including airway hyperreactivity, eosinophilic airway inflammation, mucus hypersecretion, and Ag-specific Ig production. Whereas R848 significantly reduced IL-5, IL-13, and IL-17, it induced IFN-γ and IL-27. Neutralization of IL-27 completely reversed the therapeutic effect of R848 in the experimental asthma model, demonstrating dependence of R848-mediated suppression on IL-27. In vitro, R848 induced production of IL-27 by murine alveolar macrophages and dendritic cells and enhanced expression of programmed death–ligand 1, whose expression on monocytes and dendritic cells has been shown to regulate peripheral tolerance in both murine and human studies. Moreover, in vitro IL-27 enhanced secretion of IFN-γ whereas it inhibited IL-5 and IL-13, demonstrating its direct effect on attenuating Th2 responses. Taken together, our study proves that R848-mediated suppression of experimental asthma is dependent on IL-27. These data provide evidence of a central role of IL-27 for the control of Th2-mediated allergic diseases.

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“…Furthermore, a recent report indicates that CD1c+ DCs from patients with COPD hinder T-cell effector functions and favor the generation of suppressive T cells. The authors speculate that these features of cDC might contribute to impaired immunity to respiratory viruses 46 . Though these observations may seem contradictory, they are consistent with the notion that COPD is characterized by a paradoxical combination of heightened inflammatory responses that contribute to tissue damage and reduced host defence against respiratory pathogens.…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Dendritic Cells in Human Lung Disease

Upham

Yang

2017

CHEST

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Tolerogenic signaling by pulmonary CD1c+ dendritic cells induces regulatory T cells in patients with chronic obstructive pulmonary disease by IL-27/IL-10/inducible costimulator ligand

Cited by 38 publications

References 50 publications

Dendritic Cells and Monocytes with Distinct Inflammatory Responses Reside in Lung Mucosa of Healthy Humans

Dendritic Cells and Monocytes with Distinct Inflammatory Responses Reside in Lung Mucosa of Healthy Humans

IL-27 Is Essential for Suppression of Experimental Allergic Asthma by the TLR7/8 Agonist R848 (Resiquimod)

Dendritic Cells in Human Lung Disease

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