Open AccessApoptosis‐related mitochondrial dysfunction defines human monocyte‐derived dendritic cells with impaired immuno‐stimulatory capacities
Author(s) -
Castera Laurent,
HatzfeldCharbonnier Anne Sophie,
Ballot Caroline,
Charbonnel Florence,
Dhuiege Edith,
Velu Thierry,
Formstecher Pierre,
Mortier Laurent,
Marchetti Philippe
Publication year - 2009
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2008.00358.x
Subject(s) - cd86 , cd80 , apoptosis , microbiology and biotechnology , mitochondrion , biology , programmed cell death , immune system , caspase , immunology , t cell , cytotoxic t cell , cd40 , in vitro , biochemistry
The death of dendritic cells (DCs) can potentially influence immune responses by affecting the duration of DC stimulation of lymphocytes. Here, we report that cultured mature monocyte‐derived DCs manifest early mitochondrial damage ( i.e. within 24 hrs), characterized by mitochondrial membrane potential (ψΔm) disruption and mitochondrial release of pro‐apoptotic factors, followed by reactive oxygen species (ROS) production and activation of caspases. Afterwards, DCs with mitochondrial alterations are condemned to undergo apoptosis and necrosis. Macroarray analysis results (validated by real time quantitative‐PCR (QRT‐PCR) and immunoblotting), showed up‐regulation of the pro‐apoptotic member of the Bcl‐2 family, Bim, while expression of several anti‐apoptotic molecules was down‐regulated. Importantly, pre‐apoptotic DCs (characterized by a low Δψm) showed a modified phenotype, with down‐regulation.of HLA‐DR and of the co‐stimulatory molecules CD80 and CD86. Moreover, sorted viable low ψΔm DCs were unable to activate allogeneic T cells, indicating that pre‐apoptotic DCs have already lost some of their immuno‐stimulatory capabilities long before any detectable signs of death occur. Perturbations to mitochondrial respiration with rotenone identified the same modifications to DC immune functions. These data indicate a strong requirement for mitochondrial integrity for the immuno‐stimulatory capacities of DC. Determining ΔΨm could be a useful parameter to select ‘fully’ functional DCs for anti‐tumour vaccines.