期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 134, 期 4, 页码 944-U282出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2014.05.045
关键词
Chronic obstructive pulmonary disease; dendritic cells; regulatory T cells; IL-27; IL-10; inducible costimulator ligand
资金
- Hellenic Thoracic Society
- First Department of Intensive Care Medicine of Evaggelismos Hospital
- Hellenic Ministries of Health and Education
- European Respiratory Society
- Medical Research Council [G0600879]
- British Medical Association H.C. Roscoe Fellowships
- Welcome Trust for the Centre for Respiratory Infection [083567/Z/07/Z]
- Imperial College and the National Institute for Health Research (NIHR) Biomedical Research Centre
- NIHR Clinical Lecturer
- GlaxoSmithKline
- Pfizer UK
- MRC [G0600879] Funding Source: UKRI
- Asthma UK [MRC-AsthmaUKCentre, CH11SJ] Funding Source: researchfish
- Medical Research Council [G1000758, G0600879] Funding Source: researchfish
- National Institute for Health Research [CL-2008-21-014] Funding Source: researchfish
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-beta. 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.
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