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