Download Dendritic cells at the end of the Millennium

Immunology and Cell Biology (1999) 77, 404–410
Special Feature
Dendritic cells at the end of the Millennium
M R E S C I G N O, 1 F G R A N U C C I 2 A N D P R I C C I A R D I - C A S TAG N O L I 1
1
Department of Biotechnology and Bioscience, University of Milano-Bicocca and 2CNR Cellular and Molecular
Pharmacology Center, Milan, Italy
Summary We have recently proposed a dual role for dendritic cells (DC) in the amplification of innate immune
responses and in the activation of adaptive immune responses. The DC are localized along the major routes of
entry of micro-organisms, where they perform a sentinel function for incoming pathogens. Soon after interaction
with appropriate stimuli, DC undergo a coordinated process of maturation and respond to danger signals by reprogramming their functions. The DC first regulate leucocyte recruitment at the site of inflammation, through the
production of chemokines, inflammatory cytokines and interferons, and then they acquire migratory properties and
undergo a rapid switch in chemokine receptor expression. This allows them to leave the inflamed tissue and to reach
the lymph node T cell area. During this migration, DC complete their maturation process and acquire the ability
to prime T cell responses. Thus, DC bridge innate and adaptive immunity.
Key words: antigen presentation, chemokine, dendritic cell, dendritic cell maturation, innate response.
Introduction
During recent decades, studies of the immune response have
concentrated on adaptive responses, particularly the mechanisms allowing the generation of a repertoire of antigenspecific receptors. Less effort has been made to understand
how the immune system, when generating an innate response,
is able to recognise micro-organism diversity and eventually
direct the most appropriate type of adaptive response. The
discovery of a new class of receptors (Toll-like receptors),
which are involved in the recognition of characteristic
patterns of groups of micro-organisms,1 has lead to a reevaluation of the role of the innate immune system as a discriminating system. Indeed, the induction of different types
of effector adaptive responses seems to be directed by the
innate system after recognition of particular groups of microorganisms (Fig. 1). Links between adaptive and innate immunity have been suspected and recently we have proposed that
dendritic cells (DC) are the cells bridging the two arms of the
immune system (Fig. 2). In fact, as well as their potent T cell
stimulation, a salient feature of DC function is their so-called
‘maturation’ in response to stimuli that typically signal the
presence of infection.
Dendritic cells are distributed in most tissues and, in particular, in tissues that interface with the external environment,
where micro-organisms can enter. The DC in peripheral
tissues are immature, but capable of active antigen uptake
through regulated endocytosis and phagocytosis. After exposure to micro-organisms, the maturing DC produce
chemokines, cytokines and IFN-α/β, thus indicating a role
for DC in cell recruitment and in amplifying innate
responses. Only hours after micro-organism exposure, DC
undergo a process of maturation involving the translocation
of MHC class II molecules from intracellular compartments
to the cell surface and the neo-biosynthesis of class I molecules.2,3 Matured DC also express high levels of costimulatory and adhesion molecules that favour T cell stimulation. In
addition, mature DC up-regulate particular chemokine receptors, such as CCR7, that are believed to direct DC migration
to lymphoid organs. The divergent effect of maturation
signals on the expression of different chemokine receptors
suggests a ‘weigh anchor: hoist the sail’ model for the trafficking of DC.
Evidence of the in vivo relevance of these in vitro findings
has recently been shown (C Reis e Sousa, pers. comm.,
1999). Indeed, microbial stimuli have been reported as activating DC in vivo, causing accelerated migration to the T cell
areas of lymphoid tissues, increased presentation of antigen
and up-regulation of costimulatory molecules.
The present review aims to illustrate the re-programming
of DC activity in the early and later hours following exposure
to micro-organisms or their products.
To investigate DC maturation and the signals inducing
appropriate DC priming, it is important to generate a homogeneous DC population and to maintain the cells in their
immature stage. In our laboratory, we have established
culture conditions for generating long-term, growth factordependent immature myeloid DC from either mouse spleen
or bone marrow.2 These cells possess all of the properties of
immature DC, but can be induced to full and appropriate
maturation with LPS, lipotechoic acid (LTA) or the uptake of
bacteria.
The antigen uptake function is regulated during DC
maturation
Correspondence: P Ricciardi-Castagnoli, Department of Biotechnology and Bioscience, University of Milano-Bicocca, Milan, Italy.
Email: <[email protected]>
Received 21 June 1999; accepted 21 June 1999.
When DC were first described,4 an extensive study of their
properties was hampered by their paucity in tissues and by
the difficulty of obtaining homogeneous immature DC
populations in vitro that were free of contaminating
Dendritic cells
405
Figure 1 The dendritic cell
(DC) maturation process after
encountering different groups of
micro-organisms. TLR, Toll-like
receptor.
Figure 2 Dendritic cells (DC) as a bridge between adaptive and
innate immune responses.
macrophages. Thus, because antigen uptake is a property of
immature DC, the phagocytic capacity of DC has long been
denied.5 Not only are DC better phagocytic cells when immature, but, most remarkably, DC readily increase their antigenuptake capacity 1–2 h after activation. They then
progressively reduce this capacity during the late stages of
maturation (F Granucci et al., unpubl. data, 1999). Thus, DC
control the extent of antigen internalization and limit bacterial ingestion by down-regulating phagocytosis.
Three major pathways of antigen uptake have been
described in DC: (i) phagocytosis; (ii) receptor-mediated
endocytosis; and (iii) macropinocytosis.6 Conventional
phagocytosis is the main entry for microbes, including
bacteria.7 The DC can engulf the bacteria by actively
surrounding them with pseudopodia. This process is either
started by phagocytosis-promoting receptors of the Fc type
or it is dependent on complementary signals in the case of
complement-type receptors. The movement of the pseudopodia in activated DC involves actin-binding proteins and it
can be blocked by the drug cytochalasin D, which stops the
polymerization of actin.2 In addition to the conventional
zipper-type phagocytosis, DC have been found to also use
coiling phagocytosis for the uptake of bacteria.8 Phagocytosis of bacteria may take place either via direct interaction
between microbial adhesins and phagocytic receptors (nonopsonic uptake) or indirectly via opsonins (for example, antibody or complement). These act as bridging molecules
between the microbial surface and opsonin receptors of the
phagocytes (opsonic uptake).
Dendritic cells express a number of receptors that mediate
endocytosis. These include Fc receptors (FcR), the Mac-1
(CD11b/CD18, αMβ2 integrin) molecule, CD14, DEC-205
and mannose receptors and the new family of ‘danger’ receptors called TLR (toll-like receptors; Fig. 3). The Mac-1
molecule is the CR3 complement receptor used for the
phagocytosis of complement-coated bacteria, but it can also
mediate adhesion and chemotaxis.9 It is stored in intracellular
vesicles, which are rapidly mobilized to the cell surface in
response to chemoattractants.10 The mannose receptor is a
175 kDa C-type lectin, which is expressed predominantly on
macrophages and dendritic cells, including immature DC. It
has a high affinity for carbohydrates, being involved in the
internalization and presentation of mannosylated proteins.11
CD14 has long been described as an LPS receptor, but,
lacking an intracellular transducing cytoplasmic tail, it could
not be considered as the only mediator of LPS-induced activation of DC. Very recently, the transducing receptor for LPS
has been identified in TLR 2 and 4.12,13 The TLR family of
proteins have been described as key players in triggering
innate defences against bacterial and fungal invaders.14 The
engagement of TLR 4 induces the nuclear translocation of the
nuclear factor (NF)-κΒ transcription factor14 via activation of
MyD88 and interleukin-1 receptor-associated kinase (IRAK)
and analogously, LPS-induced activation of DC is mediated
by NF-κΒ.15
406
M Rescigno et al.
Figure 3 Key molecules in early and late dendritic cell (DC) functions. MARCO/R, MARCO receptor; TLR, Toll-like receptor; ICAM,
intracellular adhesion molecule; LFA, leukocyte function-associated antigen.
Thus, receptors involved in endocytosis can be divided
into two classes by their capacity to bind pathogen-associated
molecular patterns (PAMP) either directly or indirectly by
binding complexes of PAMP and their receptors (Fig. 3).
Macropinocytosis is a process by which large pinocytic
vesicles are generated, which sample extracellular fluids and
solutes.
‘Weigh anchor: hoist the sail’
Immature DC originate in the bone marrow and migrate to
peripheral non-lymphoid tissues through the blood. Although
immature blood DC have been identified in humans, the
nature of circulating DC remains unknown. It has been proposed that blood DC may represent a reservoir of DC tissue
precursors that can extravasate to repopulate the pool of
tissue DC. Nevertheless, they can also represent a set of circulating APC that continuously sense the endothelium and
are strongly recruited at inflammation sites.16 Moreover,
regarding the origin of tissue DC from circulating precursors,
it has been observed that non-proliferating blood monocytes
can differentiate into DC after two days culture in vitro with
endothelial cells. These newly matured DC are able to reverse
transmigrate across the endothelium, similarly to when DC
enter the lymphatics. Cells that differentiate into macrophages do not have this migratory capability.17 Thus, the
endothelium per se can play a fundamental role in driving the
differentiation of macrophage and DC precursors into one
lineage or another.
Immature blood DC have a proven ability to interact
continuously with the capillary dermal endothelium. The
extravasation of leucocytes from the vasculature to the tissues
has been described as a multistep mechanism involving
selectins, chemoattractants and integrins.18 The initial adhesive step is generally mediated by selectins and α4 integrins.
Immature blood DC uniformly express a glycosylated form
of P-selectin glycoprotein ligand (PSGL)-1, able to bind
P- and E-selectins. Under flow conditions in vitro, DC constitutively tether and roll on E- and P-selectins. In vivo, DC
continuously interact with non-inflamed dermal endothelium
and are able to extravasate during an inflammatory process.16
The extravasation phenomenon is regulated by chemokines
produced by endothelial cells and surface integrins like intracellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1.
Tissue-resident immature DC constantly monitor the environment for pathogens. Their migratory ability allows them
to move, inside the tissue, toward inflammatory sites and
from the site of inflammation to draining lymph node
(through the lymphatic system), where they inform helper
and cytotoxic T cells of the incoming danger. Inside lymph
nodes, DC home in on the T cell-rich areas. Chemokines are
not only involved in controlling the extravasation processes,
but also in regulating DC movements inside non-lymphoid
tissues and toward lymphoid tissues. Chemokines are produced by leucocytes and by endothelial and epithelial cells
upon interaction with inflammatory stimuli.19 The specific
effect of chemokines on target cell types is mediated by a
family of G-protein-coupled seven trans-membrane receptors. Mouse and human DC express receptors for a number of
inflammatory chemokines (Fig. 4). Because the migratory
function of DC is tightly regulated, the expression of chemokine receptors also undergoes strict modulation during the
inflammatory process and after the receptors have reached
their final destination in the draining lymph nodes. Human,
monocyte-derived immature DC express chemokine receptors, such as CCR1, CCR2, CCR5 and CXCR1, and respond
to inflammatory chemokines, such as macrophage inflammatory protein (MIP)-1α, regulated upon activation, normal
T cell expressed and presumably secreted (RANTES) and
monocyte chemoattractant protein (MCP)-1.20,21 Thus, they
are presumably attracted at the inflammatory site via a gradient of chemokines that are able to act on chemokine receptors expressed on their surface at the immature stage (Fig. 4).
Following activation with inflammatory stimuli, such as LPS
or TNF-α, DC down-regulate the expression of CXCR1,
CCR1 and CCR520,21 and lose their ability to migrate in
response to CCR1 and CCR5 ligands (MIP-1α, RANTES and
MIP-1β) according to the model of ‘weigh anchor: hoist the
sail’.20
Dendritic cells
407
Figure 4 (a) Chemokines produced by dendritic cells (DC). (b)
Chemokine receptors expressed
by DC. TARC, thymus and activation-regulated chemokine; MDC,
macrophage-derived chemokine;
RANTES, regulated upon activation, normal T cell expressed and
presumably secreted; MIP, macrophage inflammatory protein; IP,
IFN-γ inducible protein; CCR,
C-C chemokine receptor; CXCR,
CXC chemokine receptor.
The precise kinetics of chemokine receptor regulation at
early time points after LPS activation has been examined in
murine proliferating DC.22 It has been shown that CCR1
expression and function are both first up-regulated between
30 min and 1 h after LPS stimulation and then progressively
down-modulated from 2 h after LPS interaction.22 These
kinetics correlate well with the spontaneous migration of proliferating mouse DC that is observed after LPS activation.
The DC initially down-regulate their intrinsic migration function, with a maximum effect 2 h after stimulation, and then
progressively increase it with a peak at 4–6 h after LPS treatment (F Granucci et al. unpubl. data, 1999).
In contrast, after activation, human monocyte-derived DC
strongly up-regulate the expression of CCR7, a chemokine
receptor that responds to chemokines such as secondary
lymphoid-tissue chemokine (SLC) and EBI1 ligand chemokine (ELC), which are expressed, respectively, by lymphatic
endothelial cells and by mature DC in the T cell area of
lymphoid organs.20 Slowly, activated DC acquire the ability
to respond to ELC with a maximum effect 24–48 h after the
activation stimulus. Moreover, by confocal microscopy, class
II positive cells have been shown within lymphatic channels
expressing SLC in the mouse dermis and SLC has been
described as a potent chemoattractant for migrating maturing
skin DC.23 Thus, the change in chemokine receptor expression represents one of the mechanisms for regulating the
trafficking of DC inside the inflamed tissue and movement to
lymphoid organs after antigen capture.
The expression in immature DC (and up-regulation soon
after activation) of receptors for inflammatory chemokines
may represent a system to recruit and maintain DC at inflammatory sites. Here, DC remain to perform antigen uptake and
to contribute to increase the inflammatory process in order to
recruit new leucocytes. Finally, after losing the expression or
the function of some chemokine receptors, DC can leave the
inflammatory site and reach the draining lymph nodes
through the afferent lymphatics. Expression of the CCR7
receptor allows them to be kept in the T cell area of the lymph
node.
The inflammatory process can be sustained by DC,
because they are able to produce chemokines, such as MIP1α and MIP-2, which are well-known leucocyte attractants.
In particular, it has been shown that proliferating mouse DC
strongly up-regulate the mRNA for MIP-1α and MIP-2,
beginning 1 h after LPS activation.22 It has been proposed
that the chemokines produced so early during the process of
maturation act as an autocrine loop to down-modulate the
function of receptors, such as CCR1, via a desensitization
process.22 This would allow DC to arrest at the site of inflammation, where they can recall new DC and neutrophils,
attracted by MIP-1α and MIP-2 (Fig. 4). Immature DC also
express RANTES, but its mRNA is down-regulated immediately after LPS activation and remains low during the entire
period (2–3 h) in which DC are supposed to persist at the
inflammatory site. This chemokine is finally strongly upregulated 24 h after LPS treatment, when DC have reached
the lymphoid organs. Because RANTES, like other chemokines produced by mature DC (IFN-γ inducible protein
(IP)-10 and MCP-1), is known to be active on T cells, these
observations are consistent with the idea that, at the level of
lymphoid organs, mature DC produce chemokines to attract
T cells for antigen presentation and to activate the immune
response.22 In fact, Langerhans’ cells that migrate to draining
lymph nodes from inflamed skin up-regulate the expression
of macrophage-derived chemokine (MDC; a chemoattractant
for primed T lymphocytes) and are, indeed, able to attract
activated T cells.24 It has been hypothesized that in an initial
phase, maturing DC and naïve T cells are recalled in the
T cell area of lymph nodes by chemokines such as SLC and
ELC, so that DC can prime rare antigen-specific naïve
T cells. Subsequently activated, dividing T cells are more
efficiently attracted and kept in the T cell area by newly arriving DC-producing chemokines, such as MDC.24
Molecular checkpoints in MHC class II antigen
presentation
Professional APC are characterized by their ability to process
and present antigens on MHC class II molecules. Newly
synthesized class II α and β chain assemble in the endoplasmic reticulum (ER) with a third polypeptide, invariant chain
(Ii chain), that renders MHC molecules inaccessible to peptides in the ER.25 Two pathways of antigen processing have
been described, one involving assembled MHC-Ii chain molecules and the other based on Ii-chain-free MHC II dimers
recycled from the plasma membrane. New MHC class II
molecules are stored in a special compartment designated
MHC II enriched compartment (MIIC). The MIIC were first
described in B cells26 and then in DC.27 They contain late
endosomal and lysosomal markers as well as HLA-DM or
H-2M molecules, which enhance binding of peptides to MHC
molecules. In the MIIC, MHC class II molecules are
408
M Rescigno et al.
Figure 5 Scheme of the molecular events induced after bacterial or bacterial product activation
of dendritic cells (DC). NIK,
NF-κB-inducing kinase; TAP,
transporter
associated
with
antigen processing; CIIV, class II
vesicles; MIIC, MHC II enriched
compartments.
continuously degraded and replaced by newly formed MHC
II-Ii chain assembled molecules. The basal level of neobiosynthesis of MHC II molecules is indeed sustained in
immature mouse DC.3 Depending on the maturation stages of
DC, MHC II positive vesicles, distinct from late endosomes
or lysosomes, have also been described and have been named
class II vesicles (CIIV). In these structures, MHC class II
molecules are free of the invariant chain. Interestingly, the
dynamics of these vacuoles are closely related to DC maturation and are under the strict control of Ii-chain cleavage.
Indeed, immature cells contain only MIIC compartments, in
which MHC molecules are assembled with Ii chain. During
maturation, there is a clear intermediate stage of the cells,
which is characterized by the appearance of CIIV structures
of Ii chain-free MHC II. The degradation of the Ii chain is
catalysed by cathepsin S, whose activity is under the control
of its inhibitor, cystatin C, whose level and localization are
regulated during DC maturation.28 Eventually, CIIV fuse to
the plasma membrane for exposure of MHC-peptide complexes at the cell surface, giving rise to the typical phenotype
of mature DC. Being targeted to the plasma membrane, MHC
II molecules are no longer subject to lysosomal degradation
and their half-life is increased.3,29,30 Simultaneously, maturing
DC progressively reduce neobiosynthesis and mRNA transcription of MHC II to a complete shut-off (F Granucci et al,
unpubl. data, 1999).
Against all odds: MHC class I presentation of
exogenous antigens
The MHC I molecules are expressed ubiquitously and their
major role is to display a spectrum of peptides representing
the intracellular protein composition, so as to allow continuous monitoring of the state of the cell by cytotoxic T cells (for
microbial infection as well as malignant transformation).31
The nature of the pathway of MHC class I peptide loading
has long been known to exclude the possibility that non-
endogenously produced proteins could be presented on these
molecules. Indeed, newly formed MHC I–β2-microglobulin
(β2-m) molecules assemble in the ER with at least three
proteins that ensure their stability in the absence of highaffinity peptide: calnexin, calreticulin and ERp57. This
stable complex binds to another protein, tapasin, in order to
associate with the transporter associated with antigen presentation (TAP). The TAP protein is responsible for the transport, and probably for the loading, of cytosolic peptides
generated by the activity of the proteasome on to newly
formed MHC I molecules. Thus, only those peptides that
reach the endoplasmic reticulum can associate with MHC I
molecules. After the binding of high-affinity peptides, the
accessory molecules are released and MHC I–peptide complexes are exported to the cell surface. Although a recycling
mechanism of MHC I molecules from the plasma membrane
to endocytic vesicles has been described for macrophages,32
no such mechanism has been observed in DC. However, it has
been recently shown that DC have the capacity to present
exogenously introduced antigens on MHC I molecules3,33–35
via a mechanism that is proteasome and TAP dependent
(Fig. 5). The nature of the antigen is critical for this exogenous antigen presentation on MHC I molecules. Indeed,
soluble proteins are poorly presented, whereas antigens
introduced via receptor-mediated endocytosis and phagocytosis are presented very efficiently.3,33–35 This is of major
interest, because DC can prime CTL not only to viral antigens, but also to bacterial, tumoral and other antigens that
can be internalized through mechanisms that are symptomatic of environmental ‘danger’. Interestingly, MHC I
biosynthesis is highly up-regulated by bacteria and bacterial
products,3,29 reaching a peak at 18 h when DC have acquired
full T cell stimulatory capacity (Fig. 5). Moreover, only in the
presence of bacteria, the half-life of MHC I molecules
changes from 3 to 9 h, allowing presentation of bacterial proteins for longer periods, thus increasing the chance of
meeting antigen-specific CTL.
Dendritic cells
409
Figure 6 Time frame of the
coordinated process of dendritic
cell (DC) maturation. Soon after
interaction with appropriate
stimuli, DC respond to danger
signals by stimulating a controlled
and effective immune response.
Dendritic cells first regulate
leukocyte recruitment at the site of
inflammation, through the production of chemokines and
inflammatory cytokines, and then
they acquire migratory properties
and undergo a rapid switch in
chemokine receptors. This allows
them to leave the inflamed tissue
and to reach the lymph node T cell
area. MIP, macrophage inflammatory protein; RANTES, regulated
upon activation, normal T cell
expressed and presumably secreted; MCP, monocyte chemoattractant protein; SLC, secondary
lymphoid-tissue chemokine; ELC,
EBI1 ligand chemokine.
Interestingly, concerning the classical MHC I pathway of
antigen presentation when a cell is infected with a virus and
the proteins are produced endogenously, the same set of virus
proteins is processed differently if fibroblasts or DC are
analysed.36 This agrees with the fact that LPS-activated DC
up-regulate the PA28 proteasome subunit responsible for a
change in the repertoire of peptides generated in the same
cell (F Granucci et al, unpubl. data, 1999).
Concluding remarks
Dendritic cells are characterized by dual roles: amplification
of innate immune responses and activation of the adaptive
immune responses. The DC fulfil these tasks by taking up
incoming pathogens and by undergoing a coordinated process
of maturation after interaction with appropriate stimuli. The
DC have the ability to sense the external environment and to
respond to danger signals by stimulating a controlled and
effective immune response. In this respect, DC could be considered as the conductors of the immune system.
The initial production of inflammatory cytokines and
chemokines regulates leucocyte recruitment at the site of
inflammation. On down-regulation of some chemokine
receptors and up-regulation of others, such as CCR7, DC can
leave the inflamed tissue and reach the lymph node T cell
area. Here, DC complete their maturation process and
acquire the ability to prime T cell responses (Fig. 6). The
nature of the original stimuli is likely to determine the type
of DC maturation and cytokine milieu, which may result in
different types of T cell responses.
Acknowledgements
We thank Elena Bottani for carefully editing the manuscript
and generating the figures. This work was partially supported
by CNR Finalised Project of Biotechnology, AIRC (Italian
Association Against Cancer) and Biopolo.
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