European Heart Journal (2005) 26, 1700–1704

doi:10.1093/eurheartj/ehi282
Review

Dendritic cells in atherosclerosis: current status of the

problem and clinical relevance
Yuri V. Bobryshev*
Surgical Professorial Unit, Level 5, DeLacy Building, St Vincent’s Hospital Sydney, University of New South Wales,
Darlinghurst, New South Wales 2010, Australia
Received 8 December 2004; revised 3 March 2005; accepted 24 March 2005; online publish-ahead-of-print 26 April 2005

KEYWORDS Dendritic cells (DCs) are the most potent antigen-presenting cells. DCs were identified in arteries in
Dendritic cells; 1995 and, since then, further knowledge has been gained indicating the importance of DCs in athero-
Arteries; sclerosis. Vascular DCs have been shown to become activated from a very early stage of atherosclerosis.

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Atherosclerosis; Some DCs cluster with T cells directly within atherosclerotic lesions, while others migrate to lymphoid
Plaque destabilization organs to activate T cells. Dyslipidaemia systemically alters DC function and recent findings suggest that
DCs play a role in plaque destabilization. This review summarizes the current status of the problem.

Introduction cell interactions, the presence of co-stimulatory molecules

Initially described in the skin by Langerhans in 1868, dendri-
tic cells (DCs) were identified as antigen-presenting cells in
1973 by the pioneering work of Steinman and Cohn.1 In all
tissues and all pathological conditions, DCs are minor cell
populations but they are the most potent antigen-presenting
cells.2
In arteries, DCs were originally identified in 1995.3 Since
then, knowledge has been gained indicating the importance
of DCs in atherogenesis. This review summarizes the current
status of the problem.
DCs and immunity
In recent years, the biology and pathophysiology of DCs have
been highlighted in a number of reviews and mono-
graphs.2,4–9 DCs are members of both innate and adaptive
immune systems.4–8 As members of the innate immune
system, DCs can respond to danger signals by immediately
generating protective cytokines.4–9 As the key element of
the adaptive immune system, DCs respond to danger
signals by the acquisition of the capacity to direct the devel-
opment of primary immune responses appropriate to the
type of danger.4–9 DCs have a potent antigen-presenting
capacity for the stimulation of naive, memory, and effector
T cells.4–9 DCs are capable of activating not only convention-
al T cells but also natural killer T (NKT) cells.9 During the
development of an adaptive immune response, T cells form
direct contacts with DCs and respond to peptide antigen dis-
played on major histocompatibility complex (MHC) class II
and class I molecules present on DC surfaces.4–9 In DC/T
* Corresponding author. Tel: þ61 2 8382 2395; fax: þ61 2 9314 7654.
E-mail address: y.bobryshev@unsw.edu.au
on DCs is required for T cell activation and the differen-
tiation into effector cells. In the absence of sufficient co-
stimulation, T cells contacting DCs exhibit anergy or
undergo apoptosis.4–9 In DC/T cell contacts, the secretion
or lack of secretion of cytokines, in particular interleikin-
12 (IL-12), by DCs is instrumental in the differentiation of
T cells into type 1 (Th1) or type 2 (Th2) effector T cells,
respectively.4–9
The growing interest in DC physiology reflects the import-
ance of DCs in the initiation and progression of various dis-
eases, including tumour, viral and bacterial infections, and
various autoimmune diseases.2,4–9 The ability of DCs to
elicit immune responses and the availability of DC culture
systems has led to their use in cancer immunotherapy
and therapeutic intervention in autoimmunity and
transplantation.2,4,9,10
Origin, migratory routes, and histological
nomenclature of DCs
DCs originate from a common CD34þ progenitor in the bone
marrow.4–9 Their development involves three stages for
which the terms, ‘precursors’, ‘immature’, and ‘mature’
are used.2,4–9 DC precursors circulate via the bloodstream
to reach their target tissues where they take up residence
at sites of potential antigen entry.2,4–6 In this stage, DCs
can be identified in essentially all tissues but are mostly con-
centrated along epithelial and body cavity surfaces.2,4–6 In
these locations, DCs continuously and efficiently sample
the antigenic content of their microenvironment by
phagocytosis, by high-volume fluid phase macropinocytosis,
by receptor-mediated endocytosis, or by direct contact
with necrotic, apoptotic, or virally infected cells.2,4–6
Internalized antigens are degraded into short peptides that

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DCs in atherosclerosis
are loaded onto nascent class I and class II MHC or CD1 mol-
ecules for subsequent display on the cell surface.2,4–6
Because, in this stage, DCs are not yet able to stimulate T
cells, these DCs are termed ‘immature’ or ‘processing’
DCs.2,4–6 Processing DCs exit the non-lymphoid tissues and
migrate via the afferent lymph into lymphoid tissues, such
as the spleen and lymph nodes, where DCs then complete
their maturation.2,4–6 Maturation of DCs involves the
down-regulation of endocytotic activity and the up-regu-
lation of the adhesion molecules (CD11a, CD50, CD54, and
CD58), co-stimulatory molecules (CD40, CD80/B7.1, CD86/
B7.2) and antigen-presenting molecules, including the
class I and class II of MHC proteins and CD1 molecules.2,4–6
Co-expression of the adhesion, co-stimulatory, and
antigen-presenting molecules enables DCs to form contacts
with and activate T cells.2,4–6 It has been recognized also
that the maturation of some DCs can occur in the peripheral
non-lymphoid tissues4,6 and that DCs can present antigenic
peptides to circulating T cells.4 The trafficking of DCs into
tissue sites is regulated by chemokines.2,4–6 At different
stages of their differentiation, DCs produce distinct compo-
sitions of cytokines which affect neighbouring cells.2,4–6
The histological nomenclature of DCs is rather complex. In
peripheral blood, circulating DCs are known as blood DCs.4 In
peripheral blood, circulating DCs represent the migratory
form of DC precursors. Immature DCs are known as
Langerhans cells in the skin and other epithelial surfaces
and as interstitial DCs in interstitial spaces of organs such
as the heart, kidney, and lung.2,4–6 The migratory form of
processing DCs in the afferent lymph is known as veiled
cells. Interdigitating cells in the lymphoid organs represent
mature DCs.2,4–6
The morphological appearance of DCs varies, but some
members of the DC family possess distinctive cytoplasmic
structures.4 Langerhans cells contain Birbeck granules,
while the tubulovesicular system is well developed in inter-
digitating cells.4 Accumulating evidence suggests that both
Birbeck granules and the tubulovesicular system are
involved in antigen processing and antigen presentation.4
DCs are characterized by the presence of numerous thin
cytoplasmic processes (dendrites) as well as large cyto-
plasmic veils that are continuously extended and retracted.4
The surface molecular content of DCs varies depending on
the tissue location and on the stage of cell maturation,
and DCs display either the molecules essential for antigen
capture and antigen processing or the molecules essential
for their specialized interactions with lymphocytes.2,4–6
The expression of the CD83 molecule, a member of the
immunoglobulin superfamily with unknown functions, as
well as the expression of antigen-presenting CD1 molecules
including CD1a, CD1b, CD1c, and CD1d are essentially
restricted to DCs.4 Fascin (55 kDa actin-bundling protein)
is a reliable cytoplasmic marker for identifying different
DC subtypes, while Lag-antigen and Langerin are uniquely
present in Birbeck granules and Birbeck granule-associated
structures in Langerhans cells.4 S100 (S100A1 and S100B)
proteins, the function of which in DCs are poorly under-
stood, are expressed intensely by both mature and imma-
ture DCs. The cell adhesion molecule E-cadherin is
expressed by only some subsets of DCs.4
Three pathways by which the CD34þ DC precursor can
develop into immature DCs have been recognized.2,4–6 The
first pathway leads to the differentiation of typical
1701
Langerhans cells which express E-cadherin and contain
Birbeck granules with Lag-antigen/Langerin. This pathway
is regulated by granulocyte macrophage colony stimulating
factor (GM-CSF) and tumour necrosis factor a (TNF a). The
second is a monocyte-related pathway.2,4–6 This pathway
does not yield typical Langerhans cells in the presence of
GM-CSF and TNF a, but leads to interstitial DCs displaying
high levels of CD14 and CD68 during their development.
The third is a lymphoid pathway which provides DCs for
the thymus medulla and the T cell areas of lymphoid
tissues. This subset of DCs lacks the myeloid marker
CD11b. ‘Myeloid’ DCs are required for T cell activation
whereas ‘lymphoid’ DCs induce T cell tolerance.2,4 The
development of different DC subsets is influenced by
varying combinations of cytokine growth factors, including
TNF family members (TNF-a, TRANCE/RANK), GM-CSF, IL-4,
stem cell factor, transforming growth factor-b, and flt-3
ligand.2,4–6
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DCs in the non-diseased arterial wall
Small numbers of DCs, predominantly localized along the
endothelium in the subendothelial layer, are present in the
intima of apparently normal, non-diseased arteries.3,11
Electron microscopy revealed that the normal arterial
intima harbours a distinct subtype of the DC family display-
ing unique ultrastructural features.3,11,12 Vascular DCs,
through their processes, form focal networks in some
intimal areas.13 Wick et al. 14,15 have suggested that in the
normal intima, DCs are a key element of the so-called
vascular-associated lymphoid tissue (VALT). VALT is
analogous to the mucosa-associated lymphoid tissue of the
respiratory and gastrointestinal tracts.14 VALT consists of
aggregates of vascular DCs, T cells, and resident macro-
phages distributed throughout the subendothelial layer of
the arterial intima along the luminal endothelial mono-
layer.15 It has been suggested that VALT screens ‘vascular
tissue’ for potentially harmful antigens.14,15 Besides their
intimal location, small numbers of resident vascular DCs
are present also in the adventitia, usually in close proximity
to capillaries forming the vasa vasorum.16
Vascular DCs in pre-atherosclerotic stage
The numbers of vascular DCs in the intima of athero-
sclerosis-prone and atherosclerosis-resistant areas of the
non-diseased aorta have been assessed and it has been
found that, in atherosclerosis-prone areas, there were
more DCs than in atherosclerosis-resistant areas.17 In ather-
osclerosis-prone areas, DCs were found to form cell clus-
ters.17 The accumulation of DCs has also been identified in
the intima of the carotid arteries of children, 8 weeks to
10 years of age, at sites subjected to major haemodynamic
stress and predisposed to the development of atherosclero-
sis.18 In other pathological conditions, the accumulation of
clustering DCs is thought to be an indicator of autoimmune
processes.2,4 According to the autoimmune hypothesis of
atherosclerosis proposed by Wick et al.,14 VALT activation
by auto-antigens is responsible for initiating immune
responses in the arterial wall which lead to atherosclerotic
alteration. The observations of DCs accumulating and clus-
tering in atherosclerosis-prone areas of the normal aorta
and carotid arteries3,15,17,18 support the concept that
1702
immune mechanisms are involved in the formation of ather-
osclerotic lesions from the very early stages of the
disease.19–21
DCs in atherosclerotic lesions
In atherosclerotic arteries, the number of DCs
increase.11,22–24 Vascular DCs residing in the intima
become activated in the earlier stages of atherosclero-
sis.17,22,25 Advanced atherosclerotic plaques become
enriched by DCs invading the atherosclerotic plaques from
the adventitia, along with neovascularization associated
with vasa vasorum.26 In addition to these originally resident
vascular DCs, atherosclerotic plaques may be invaded by
blood DCs via inflamed neovessels.22,26 Monocytes that infil-
trate the intima from the very early stages of atherosclero-
sis27 may contribute to an increased DC population, as well.
Depending on the micro-environmental conditions such as
the content and composition of cytokines, monocytes
migrating through the luminal endothelial monolayer from
the blood may differentiate into macrophages or into
DCs.28 DC adhesion and migration are modulated by
changes in endothelial function.29 In vitro experiments
have revealed that DC adhesion and transmigration are
markedly increased after exposing endothelial cells to
hypoxia, oxidized low density lipoproteins, and TNF-a.29
The inhibition of endothelial NO synthase increases DC
binding and transmigration, while the augmentation of
endothelial NO synthase activity has been found to
prevent DC adhesion.29 These findings suggest that the
adhesion and migration of DCs are increased by stimuli
known to accelerate atherogenesis.29
Accumulating evidence supports a view that, in the arter-
ial wall, DCs are involved in antigen capture and antigen
processing, as are DCs in other peripheral tissues.22,26,30 It
has been suggested that the migratory routes of vascular-
associated DCs are similar to those known for Langerhans
cells in the skin and DCs in other peripheral tissues.22,26
After engulfing antigen in the arterial wall, vascular DCs
likely migrate as veiled cells via the afferent lymph into
regional lymph nodes where they activate T cells.
Supporting this possibility are the immunohistochemical
observations showing that the number of interdigitating
cells in para-aortic and jugulodigastric lymph nodes
attached to atherosclerotic arterial wall segments exceed
those in the lymph nodes attached to non-atherosclerotic
arterial segments.22 Besides their migration to lymph
tissues, it has been suggested that some DCs emigrate to
the blood stream.30
An experimental in vivo study revealed trafficking of
monocyte-derived cells from atherosclerotic plaques
during lesion regression but little emigration was detected
from progressive plaques, suggesting that the progression
of atherosclerotic plaques may result not only from robust
monocyte recruitment into arterial walls but also from
reduced emigration of these cells from lesions.30 This is in
agreement with a histopathological study of human arterial
tissue which indicated that only some DCs may migrate to
the lymph nodes while other DCs may activate T cells
directly within the intima.26 Mapping of the distribution of
DCs in human atherosclerotic lesions revealed that DCs are
most frequent in areas enriched with T cells and, particu-
larly so, within inflammatory infiltrates where DCs are
Y.V. Bobryshev
found to cluster with T cells.26 DCs clustering with T cells
display the intercellular cell adhesion molecule-1 and vascu-
lar cell adhesion molecule-1,26 interactions of which with
leukocyte function-associated antigen-1 and very late acti-
vation antigen-4, respectively, are essential for T cell acti-
vation.31 In DC–T cell interactions, DCs display CD4032 and
express high levels of HLA–DR.26 Vascular DCs also express
DC-SIGN33 and some DCs display CD83, a marker of DC acti-
vation.22 In atherosclerotic lesions, DCs express not only
high levels of class II MHC molecules but also display on
their surfaces CD1 molecules,3,25,26,34 which have been
recognized as antigen-presenting molecules in the same
sense as the classical MHC class I and II molecules.35,36 It
has been found also that CD1d, an antigen-presenting mol-
ecule responsible for the presentation of lipid antigens,35,36
is expressed in atherosclerotic lesions25,34,37 and that its
expression is restricted to DCs.25 The effects of the athero-
sclerotic environment on DCs are still poorly studied but it
has been shown that in atherosclerotic lesions, DCs are
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activated and display an abundance of heat shock protein-
70.25 In contrast to other members of the DC family, the
pathophysiological significance of DCs as pro-
inflammatory and auto-immune cells in atherosclerosis
is poorly understood.
Atherosclerosis displays features of immune activation
both locally and systemically.19–21 Angeli et al. 38 demon-
strated that dyslipidemia associated with atherosclerotic
disease systemically alters the DC function. In different
pathophysiological conditions, inflammatory cytokines and
chemokines are known to be responsible for DC
activation and migration,2,4–9 but the peculiarities of the
effects of cytokines and chemokines on DCs in
atherosclerosis have not yet been investigated. Nicotine,
which is known to accelerate atherosclerosis development,
activates DCs and augments their capacity to stimulate T
cell proliferation and cytokine secretion.39 Modified lipopro-
teins accumulating in atherosclerotic lesions likely trigger
DC activation, especially as in in vitro studies, oxidized
low density lipoproteins have been shown to promote
mature DC transition from monocytes40 and induce promi-
nent DC clustering.41 C1q, which is thought to be involved
in capturing immune complexes in the lymphoid tissue, has
been found to be expressed by vascular DCs.42
DCs populating atherosclerotic lesions might be involved
in the regulation of innate immunity in athero-
sclerosis,43–45 especially as the presence of Chlamydia
pneumoniae has been identified in the cytoplasm of vascular
DCs.45 Spanbroek et al. 46 reported the expression of
5-lipoxygenase by DCs in atherosclerotic lesions.
5-lipoxygenase pathway is the major source of potent pro-
inflammatory leukotrienes issued from the metabolism of
arachidonic acid.47 These lipid mediators released by vascu-
lar DCs may act as physiological autocrine and paracrine sig-
nalling molecules and play a central role in regulating the
interaction between innate and adaptive immunity.46 The
expression of C1q by vascular DCs42 may also relate to
innate immunity in atherosclerosis.
DCs and plaque destabilization
In atherosclerotic plaques, the number of DCs markedly
increases with more than 90% of DCs accumulating in
plaque shoulders, which represent plaque rupture-prone
DCs in atherosclerosis
regions.26,48 Yilmaz et al. 48 have found that up to 70% of DCs
in the shoulders of vulnerable carotid plaques express
markers of DC activation such as CD83 and DC-LAMP. The
clustering of T cells with activated DCs cells has been
observed in plaque rupture-prone regions.26,48 In these
regions, DCs form contacts not only with conventional T
cells but also with NKT cells.49 It has been suggested that
the formation of clusters of DCs with T cells in rupture-
prone regions is associated with plaque destabilization.48,49
A comparison of DC numbers in atherosclerotic plaques
obtained from patients with and without acute ischaemic
symptoms has revealed that DC numbers are markedly elev-
ated in patients with acute ischaemic symptoms.48 Yilmaz
et al. 48 have also reported that in statin-treated patients,
atherosclerotic plaques contain significantly lower numbers
of DCs than plaques in patients without statin treatment.
In vitro experiments have revealed that statins inhibit the
maturation and antigen-presenting function of DCs, thus
possibly contributing to the beneficial effects of statins in
atherosclerosis.50
Recently, Ranjit et al. 51 have reported that, in patients
with unstable angina pectoris, DCs were functionally
altered. In contrast to healthy donors, DC co-stimulatory
molecule CD86 was upregulated in patients with unstable
angina.51 The abilities of DCs to stimulate T cells and
produce cytokines also differed in the cells obtained from
patients with unstable angina and from healthy donors.51
DCs and therapeutic intervention
in atherosclerosis
DCs may be used for the suppression of damaging immune
responses in atherosclerosis.52 Approaches in atherosclerosis
immunotherapy might be similar to those employed nowa-
days for cancer immunotherapy.4,53,54 One of these is
based on a technique in which DCs, isolated from the periph-
eral blood, are activated (‘pulsed’) with the appropriate
antigen ex vivo and then the ‘pulsed’ cells are returned to
the bloodstream.4,53
In atherosclerosis, the nature of the antigen(s) respon-
sible for the activation of T cells is still not well under-
stood.19,20 For atherosclerosis immunotherapy, DCs
obtained from the peripheral blood can be pulsed ex vivo
by cultivating them in a medium containing a total extract
or suspension of atherosclerotic plaque material. Such culti-
vation would imitate the activation of DCs occurring in
plaques in vivo. In contrast to cancer immunotherapy,
immune responses in atherosclerosis need to be suppressed.
As the presentation of peptide–MHC complexes to T cells by
DCs in the absence of co-stimulatory signals leads to anergy
and apoptosis of T cells, co-stimulatory molecules on pulsed
DCs should be blocked ex vivo prior the cells being returned
to the bloodstream. Recent achievements in developing the
techniques for the suppression (ligation) of co-stimulatory
molecules and for the loading of DCs with antigens have
made it possible to generate DCs with desirable properties.4
Recent studies indicate that NKT cells aggravate athero-
sclerosis.19 DCs may represent a useful tool for the regu-
lation of NKT cell function in atherosclerosis. In one cancer
immunotherapy technique, DCs pulsed with aGalCer ex
vivo are returned to the bloodstream.55,56 For atherosclero-
sis immunotherapy, co-stimulatory molecules on DCs pulsed
1703
with aGalCer need to be ligated prior to returning them to
the bloodstream.
Concluding remarks
DCs are present in their immature forms in non-diseased
arteries and become activated during atherogenesis. Some
DCs cluster with T cells directly within atherosclerotic
lesions, while others migrate to lymphoid organs to activate
T cells. The identification of activated DCs in atherosclerosis-
like lesions in animal models57–59 may facilitate the
investigation of the functions of vascular DCs and their use
for atherosclerosis immunotherapy.
Acknowledgement
I would like to thank St Vincent’s Clinic Foundation, Sydney, for sup-
porting this work.
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