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J Allergy Clin Immunol. 2014 Oct;134(4):944-954.e8. doi: 10.1016/j.jaci.2014.05.045. Epub 2014 Jul 19.

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.

Author information

1
First Department of Intensive Care Medicine, Evaggelismos Hospital, University of Athens Medical School, Athens, Greece. Electronic address: tsoumak@yahoo.gr.
2
Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
3
First Department of Intensive Care Medicine, Evaggelismos Hospital, University of Athens Medical School, Athens, Greece.
4
Thoracic Surgery, Sotiria Chest Hospital, Athens, Greece.
5
Airway Disease Infection Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
6
Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece. Electronic address: gxanthou@bioacademy.gr.

Abstract

BACKGROUND:

Increased mortality rates in patients with chronic obstructive pulmonary disease (COPD) are largely due to severe infectious exacerbations. Impaired respiratory immunity is linked to the enhanced susceptibility to infections. Dendritic cells (DCs) direct host immune responses toward immunity or tolerance. Pulmonary CD1c(+) DCs elicit robust antiviral immune responses in healthy subjects. Nevertheless, their functional specialization in patients with COPD remains unexplored.

OBJECTIVE:

We sought to better understand the mechanisms that suppress respiratory immunity in patients with COPD by examining the immunostimulatory and tolerogenic properties of pulmonary CD1c(+) DCs.

METHODS:

We analyzed the expression of costimulatory and tolerogenic molecules by pulmonary CD1c(+) DCs from patients with COPD (CD1c(+)DCCOPD) and former smokers without COPD. We isolated lung CD1c(+) DCs and determined their ability to stimulate allogeneic T-cell responses. The suppressive effects of lung CD1c(+) DCs and CD1c(+) DC-primed T cells on mixed leukocyte reactions were examined. An experimental human model of COPD exacerbation was used to investigate the levels of critical immunosuppressive molecules in vivo.

RESULTS:

CD1c(+) DCs from patients with COPD hinder T-cell effector functions and favor the generation of suppressive IL-10-secreting CD4(+) T cells that function through IL-10 and TGF-β. IL-27, IL-10, and inducible T-cell costimulator ligand signaling are essential for CD1c(+)DCCOPD-mediated differentiation of IL-10-producing suppressive T cells. Exposure of lung CD1c(+) DCs from nonobstructed subjects to lungs of patients with COPD confers tolerogenic properties. IL-27 and IL-10 levels are increased in the lung microenvironment on rhinovirus-induced COPD exacerbation in vivo.

CONCLUSION:

We identify a novel tolerogenic circuit encompassing suppressive CD1c(+) DCs and regulatory T cells in patients with COPD that might be implicated in impaired respiratory immunity and further highlight IL-10 and IL-27 as potent therapeutic targets.

KEYWORDS:

Chronic obstructive pulmonary disease; IL-10; IL-27; dendritic cells; inducible costimulator ligand; regulatory T cells

PMID:
25051954
DOI:
10.1016/j.jaci.2014.05.045
[Indexed for MEDLINE]

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