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INTRODUCTION
migrate out of the tissues to reach secondary lymphoid organs. Concomitant with
the modifications of their antigen presentation abilities, maturation also induces
massive migration of dendritic cells out of peripheral tissues (2). Modifications
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until phagocytic Langherans cells (LCs) were shown to be precursors of some den-
dritic cells found in lymphoid organs, and bone marrow-derived dendritic cells at
an early stage of their development were shown to internalize particulate antigens
(7). Tissue dendritic cells capture pathogens, infected cells, dead cells, or their de-
rived products to use for antigen presentation. Interestingly, pathogen recognition
and uptake are in many cases accompanied by activation/maturation of dendritic
cells. Conversely, dendritic cells are also exploited by many pathogens as a route
of entry for infection.
Receptor-Mediated Endocytosis
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ates antigen capture, transport to endosomes and lysosomes, and efficient antigen
presentation (21). The MMR is also expressed on blood dendritic cells and inter-
stitial dendritic cells in the dermis, but not on LCs.
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Mouse DEC205 was first described on mature dendritic cells, LCs, and thymic
epithelial cells (22). In contrast to the MMR, which recycles between the plasma
membrane and early endosomes, DEC205 follows an unusual intracellular path-
way after internalization, passing through late endocytic compartment (26), thanks
to a specific molecular motif (EDE) in DEC205 cytoplasmic tail, which allows ef-
ficient antigen presentation. In humans, DEC205 (also known as gp200MR6) was
only reported in blood dendritic cells, and its function is not yet documented
(27).
Dendritic cellspecific ICAM3-grabbing nonintegrin (DC-SIGN) and Langerin
are two type II lectins with mannose specificity, expressed on interstitial dendritic
cells and LCs, respectively and exclusively (28, 29). Unlike DC-SIGN, which is
more implicated in adhesion processes (see Pathogens Use Dendritic Cell Endo-
cytic Receptors), Langerin induces the formation of a unique endocytic compart-
ment of LCs, Birbeck granules (28).
ture dendritic cells and Langherhans cells play a critical role in the dissemination
of viruses from mucosae to draining lymph nodes. In this context, different den-
dritic cell surface molecules serve as virus, parasite, or yeast receptors. Measles
virus interacts with dendritic cells via FcRs or CD46 (55), when other viruses, like
SV40, enter cat dendritic cells through caveolae (i.e., specialized cholesterol-rich
membrane domain) (56). Parasites like Leishmania major infect LCs via CR3 (57),
and Histoplasma capsulatum yeasts are phagocytosed via very late antigen-5 (58).
The most extensively studied example of pathogen internalization in dendritic
cells is HIV. The question of the susceptibility of dendritic cells to infection by
HIV has been controversial, and dendritic cells now appear as Trojan Horses,
transporting viruses to lymph nodes for T cell infection and virus dissemination
(59). Interestingly, the HIV receptor (CD4) and coreceptor (CCR5 and CXCR4
chemokine receptors) are differentially expressed on dendritic cell subpopula-
tions (60). CCR5 (a receptor for M tropic strains) is expressed on fresh LCs,
whereas CXCR4 (a receptor for T tropic viruses) can be found on mature dendritic
cells (61). In addition, interstitial dendritic cells, but not mucosal dendritic cells,
express DC-SIGN, a surface dendritic cell molecule involved in HIV binding and
trans-infection of T cells (62). The normal function of DC-SIGN is to help den-
dritic cellT cell interactions and dendritic cell emigration out of blood or lymph
vessels through its interaction with ICAM-3 and ICAM-2, respectively (29, 63).
tions resulting in dendritic cell migration toward secondary lymphoid organs is only
summarized. The functional consequences of dendritic cell maturation in terms of
antigen presentation and T cell stimulation is discussed in subsequent chapters.
(iii) CD4+ T cells induce dendritic cell maturation both in vivo [for the initiation
of certain cytotoxic T lymphocytes (CTLs) responses; see DC Maturation
and T Cell Priming] and in vitro. Triggering of CD40 by CD40L on T cells
induces dendritic cell maturation (75, 76), but CD40-independent mecha-
nisms also exist. Indeed, triggering of Fas and OX40L on dendritic cells by
FasL and OX40, respectively, on T cells may induce functional maturation
(77, 78) (see Do T Cells Regulate Dendritic Cell Half-Life?).
(iv) Dendritic cells may also be activated through receptors for immunoglob-
ulins (see Receptor-Mediated Endocytosis). Indeed, engagement of most
FcR, including Fc RI, Fc RIII, Fc RI, and Fc R, by immune complexes
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or specific antibodies, induces dendritic cell maturation (11, 12, 79). This
process requires the FcR-associated -chain that contains an immunore-
ceptor tyrosine-containing activation motif (ITAM). Tyrosine phosphoryl-
ation of this motif may initiate dendritic cell maturation.
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(v) Cell death can be sensed as a danger signal by dendritic cells. Shi et al.
showed that cell injury releases adjuvant compounds that enhance T cell
responses (80). Two studies showed that necrotic, but not apoptotic, cell
death induces mouse and human dendritic cell maturation in vitro (40, 41),
although another study found that apoptotic bodies may induce dendritic
cell maturation (81). One should be careful in interpreting these results,
however, because LPS, mycoplasma contamination (82) or CD40L ex-
pression by apoptotic bodies (83) could be responsible for dendritic cell
maturation. The nature of the dendritic cell activating compounds is still
unclear. Nucleotides, such as ATP and UTP, may activate dendritic cells
through purinergic receptors (5). Hsps including gp96, hsp90, and hsc70
are released by necrotic cells and may induce dendritic cell maturation
(84, 85). Although CD91 has recently been identified as a gp96, hsc70,
and hsp90 receptor, its role in dendritic cell activation has not yet been ex-
plored. Hsp60 and hsc70 activate macrophages through CD14 and/or TLR
(8689), but receptors engaged on dendritic cells are not characterized.
It is unlikely that all these pathways for dendritic cell maturation are redundant.
Rather, they probably result in functionally distinct dendritic cell populations. In
addition, different activation signals may act synergistically or regulate each other.
For example, human TGF--untreated dendritic cells are activated by LPS or TNF-
in contrast to TGF--treated monocyte-derived dendritic cells, which require a
CD40-dependent signal to acquire high T cell stimulating activity (90).
because dendritic cells from Mkk3 (a p38 activator)-deficient mice fail to produce
IL-12 in response to CD40 stimulation (95).
Calcium-ionophore treatment can also induce phenotypical and functional mat-
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uration of monocytic cells (96). Although LPS, TNF- and calcium ionophore sig-
naling pathways all lead to NF-B activation, only the calcium ionophore involves
calmodulin/calcineurin activation (96).
Recent results point at MyD88 as an essential component of TLR signaling in
dendritic cells (97). Not all TLR, however, activate a MyD88-dependent signaling
pathway. In the absence of MyD88, TLR2- and TLR9-induced dendritic cell mat-
uration is completely abolished, whereas TLR4, after LPS binding, can still induce
full dendritic cell maturation (98, 99). A MyD88-independent pathway involving
MAPK and NF-B pathways therefore exists downstream of TLR4 (98).
Finally, FcRI triggering in LCs induces phosphorylation of the tyrosine ki-
nase syk and Ca++ mobilization (12). We found recently that Fc R engage-
ment in mouse dendritic cells induces syk and ERK phosphorylation and that
syk is indispensable for immune complexinduced dendritic cell maturation
(C. Sedlik, D. Orbach, E. Schweighoffer, F. Colucci, S. Verbeek, P Ricciardi-
Castagnoli, V.L.J. Tybulewicz, J. Di Santo, S. Amigorena, in preparation). The
process of dendritic cell maturation is intimately linked to their migration out
of peripheral tissues toward lymph nodes. Dendritic cell migration is due to co-
ordinated changes in dendritic cell adhesion properties (changes in cytoskeleton
organization and integrin expression were reported) and in chemokine receptor
expression (100). Importantly, trans-endothelial migration itself participates in
dendritic cell differentiation and maturation (101). Although many studies have
analyzed dendritic cell maturation in vitro and in vivo, a coherent picture recon-
ciling all these studies with the physiological process of dendritic cell maturation
has yet to emerge. The precise coordination between the phenotypical, morpho-
logical, and functional modifications induced during maturation and the migration
of dendritic cells is unclear. It was initially proposed that only fully mature den-
dritic cells migrate efficiently. However, it is now clear that in many cases final
maturation requires dendritic cell interaction with T cells. It is unlikely that den-
dritic cells encounter specific T cells in the periphery. Thus, it is most likely that
dendritic cells leave peripheral tissues in an intermediate stage of maturation and
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become fully mature in the draining lymph nodes, under the control of specific
T cells.
class I molecules in the endoplasmic reticulum (ER). This model accounts, at the
effector level, for the selective killing by MHC class Irestricted CD8+ CTLs of
virus-infected cells (expressing endogenous viral antigens), but not of neighboring
cells that have internalized inactive virus or apoptotic infected cells. This model,
however, is also in conflict with experiments from M. Bevan, who demonstrated,
over 20 years ago, that priming of CTL immune responses in vivo can occur after
presentation of exogenous antigens by MHC class I molecules (a phenomenon
that he called cross priming) (102). Recent studies in dendritic cells (and other
APCs) reconcile these two series of studies by showing that, in addition to MHC
class II, internalized antigens may also be presented by MHC class I molecules
(a phenomenon referred to as cross presentation).
loaded with endogenous peptides. Loading of gp96 with peptides, for example,
occurs in the ER and is TAP dependent (124). Hsps are released upon necrotic
cell death (84) and may be internalized by APCs through specific receptors, such
as CD91 (16, 18). Hsp-associated peptides are then somehow transferred to MHC
class I and class II molecules for antigen presentation (125, 126). Blocking hsp up-
take through CD91 prevents cross presentation, suggesting that receptor-mediated
uptake is required (125). Antigens associated to different bacterial products [in-
cluding OmpA (72), Shiga toxin (127), and the CyaA toxin (128)] too, enter cells
through specific receptors and induce efficient cross presentation.
Whether receptors only accumulate antigens within dendritic cells or whether
cross presentation requires targeting of antigens to specific endocytic compart-
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ments is unknown. The wide variety of receptors that seem to promote cross
presentation could favor the first possibility. It is possible, however, that receptors
selectively drive antigens to specific endocytic cross presentation compartments.
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epithelial (137) or liver sinus endothelial cells (138) also present, although inef-
ficiently, soluble OVA by MHC class I in a TAP-dependent fashion. It is most
likely that, depending on the antigen, the cell type, and the route of internaliza-
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tion, peptide loading may occur in endosomes, the ER, or both. It is interesting,
nevertheless, that in vivo cross priming was mostly dependent on TAP (139, 140),
suggesting that antigen delivery to the cytosol might be required for the initi-
ation of CTL immune responses in vivo (see T Cell Stimulation by Dendritic
Cells).
dendritic cells. In some murine bone marrowderived dendritic cells, MHC class
II haplotypes with a strong affinity for Ii remain associated in lysosomes with a
partially degraded form of Ii, termed Iip10, that blocks access to the peptide bind-
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ing groove (149, 150). Low protease activity of cathepsin S, the main protease for
Iip10 degradation in dendritic cells (151153), is involved here, and a role of the
cathepsin S inhibitor cystatin C, specifically localized in lysosomal compartments
together with cathepsin S, Ii, and MHC class II in immature dendritic cells, has
been proposed (150).
This type of regulation, however, is not general to all dendritic cells because it
has not been observed in immature murine dendritic cells expressing other MHC
haplotypes with lower affinity for Ii (151, 154), nor in murine dendritic cells ob-
tained from different sources or cultured in different conditions (155), nor in human
dendritic cells (105, 146). In these cases, Iip10 is degraded in lysosomes, and MHC
class II dimers then reach the cell surface in association with either antigenic pep-
tides, or the CLIP peptide derived from Ii (105, 151, 155), or without any peptide
(156). Once at the cell surface, MHC class II molecules are rapidly internalized
and can associate with new peptides in recycling endosomes before going back
to the cell surface (156, 157), or they are directed to lysosomes, where they will
finally be degraded (105, 155). This pathway results in a short-term presentation of
MHC/peptide complexes at the immature dendritic cell surface, which is probably
not sustained enough to stimulate T cells efficiently.
Maturation signals induce a coordinate modification of all these aspects of
MHC/peptide complex formation and transport. MHC class II synthesis is tran-
siently upregulated (104, 105), and protease activity of the cathepsins involved in
antigen and in Ii degradation quickly increases, maybe due to their relocalization
to more acidic compartments (146). As a result, the numbers of available peptides
and of MHC dimers free to form complexes increase concomitantly. MHC/peptide
complexes are then rapidly formed (145) and transported to endosomal vesicles
(149), where they colocalize with costimulatory (B7-2) and MHC class I molecules
before being delivered to the cell surface as clusters of molecules involved in T
cell stimulation (158). During maturation, the endocytosis activity also decreases,
and transport of internalized MHC class II molecules to lysosomes for degradation
is greatly reduced, resulting in stabilization of MHC class II/peptide complexes
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at the cell surface (105, 155). Later on, MHC class II synthesis is downregulated,
and association of peptides with newly synthesized MHC molecules becomes very
inefficient, focusing the range of peptides displayed at the mature dendritic cell
surface to those arising from antigens encountered before or during the induction of
maturation. Interestingly, however, fully mature dendritic cells can still form new
MHC/peptide complexes using MHC molecules recycling from the cell surface
(157).
Anti-inflammatory cytokines can interfere with the regulation of MHC class
II processing pathways in dendritic cells. M-CSF induces a rapid and sustained
upregulation of MHC class II synthesis and transport to the cell surface in human
immature dendritic cells, but without stabilizing them at the cell surface; the re-
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sulting dendritic cells are therefore very inefficient T cell stimulators (159). IL-10
inhibits the rise in protease activity induced by maturation signals by increasing the
endosomal pH, and therefore it induces a long-term inhibition of antigen process-
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ing and presentation by mature dendritic cells (146). The cytokine environment of
dendritic cells, when they receive a danger signal, is therefore a crucial factor in
determining the orientation of the induced immune response.
NK1.1 receptor (169). The current idea is that -GalCer mimics an antigenic lipid
of cellular origin (170), which associates with CD1d in the endocytic pathway
(171). Other T cells, negative for the invariant TCR and NK1.1, recognize CD1d
molecules that have formed a complex with endogenous lipids inside the ER (171).
Very hydrophobic peptides may also form complexes with CD1d (172).
Scarce data on the specific function of CD1d expression on dendritic cells
are available. In human, NKT cells stimulated via CD1d on myeloid dendritic
cells induce dendritic cell lysis (173), thereby probably modulating the normal
immune response. In mice, CD1d-mediated interaction between NKT cells and -
GalCer-pulsed dendritic cells induces IL-12 production by dendritic cells (174) and
subsequent activation of both CD4+ and CD8+ T cells (175). We have recently
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observed that stressed murine dendritic cells, because they upregulate B7, can
activate NKT cells by presenting self-antigens in a CD1d context, whereas in
resting dendritic cells, inhibitory signals delivered upon MHC class I recognition
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membrane vesicles (exosomes) secreted by living cells may also promote cross
presentation in vivo (see Antigen Presentation and Cross Presentation).
Lymph noderesident dendritic cells might also cross present migrating den-
dritic cells. This is suggested by the efficient presentation of antigens present on
subcutaneously injected dendritic cells by MHC class II from host-derived mature
dendritic cells in the T cell areas of the draining lymph nodes (42). Surprisingly,
however, in F1 mice immunized with parental MHC-bearing dendritic cells, the
responses are mainly restricted by the MHC allele from the injected dendritic
cells, indicating that this phenomenon does not account for efficient T cell priming
in vivo (178).
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found in thymus and blood and seem to be of lymphoid origin (210). When cul-
tured in IL-3, these dendritic cells activate Th2 cells, whereas monocyte-derived
dendritic cells activate Th1 cells (221).
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sufficient to confer to APCs the ability to prime CTLs (230232). CD40 ligation
is sufficient to drive the maturation of dendritic cells (76) and confer on them the
ability to prime CD8+ T cells (75). The licensing effect of CD40 ligation was also
demonstrated upon injection of antigen-loaded dendritic cells (233). Moreover,
CD40 ligation can also overcome the tolerogenic effect of optimal-length peptide
administration, giving rise to a great interest in manipulating this pathway in the
field of cancer vaccines (234). This mechanism allows a temporal dissociation
of CD4+ and CD8+ antigen-specific T cell interaction with the dendritic cells:
Once licensed by CD4+ T cells, dendritic cells become competent to prime CD8+
T cells. This model bypasses the requirement for an improbable simultaneous
encounter of antigen-bearing dendritic cells with antigen-specific CD4+ and CD8+
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T cells.
CD4+ T cell help may also occur in a CD4+ T celldependent, CD40-indepen-
dent manner (235), as in the case of some anti-viral responses (227), possibly by the
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by dendritic cells:
1. Human monocytederived dendritic cells matured by either CD40L (243),
IFN- LPS, oligo CpG nucleotides (244), or double-stranded RNA (106)
produce high levels of IL-12 and induce Th1 cells. Nevertheless, stimuli like
PGE2 may favor the differentiation of mature monocyte-derived dendritic
cells priming Th2 cells (74). The concept of polarized maturation is now
widely conforted by the growing list of factors that allow the generation of
mature IL-12-nonsecreting dendritic cells, such as PGE2, 2-agonists, TGF-
, IL-1, TNF-, and Fas engagement (74, 219). Moreover, certain dendritic
cell costimulatory molecules, such as OX40L, can deliver a Th2 polariz-
ing signal to CD4+ T cells (219). Importantly, human plasmacytoid den-
dritic cells mature and secrete high doses of IL-12 and IFN- upon viral
infection and prime Th1 differentiation (through the induction of IFN- in
human CD4+ T cells). They correspond to the previously described nat-
ural interferon producing cells (210, 245247). Finally, monocyte-derived
and plasmacytoid dendritic cells regulate each other: IFN- favors DC1 dif-
ferentiation and inhibits IL-12 production, thus promoting Th2 responses,
whereas IL-4 induces apoptosis of preDC2, thus favoring DC1differentiation
and IL-12 production (219).
2. Pathogen-derived signals appear to play a crucial role in the regulation of cy-
tokine secretion by dendritic cells. For example, Toxoplasma gondii extracts
induce IL-12 production by murine CD8 + dendritic cells in vivo and sensi-
tivity to CD40 stimulation. However, a prolonged stimulation by the extracts
paralyses IL-12 production by dendritic cells (65, 248). Candida albicans,
at the yeast stage, induces IL-12 production and Th1 protective responses
in vitro and in vivo. At the hyphae stage, the same fungus induces dendritic
cells to stimulate IL-4 secretion by T cells and no protective responses (31).
3. Tissue-specific environmental factors may participate in the phenotypic dif-
ferentiation of dendritic cells. In mouse, CD11c+ dendritic cells purified
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from Peyers patches or lung, but not spleen, produce IL-4 and IL-10 and
preferentially induce in vitro Th2 polarization (249, 250).
4. Dendritic cell/T cell ratio (251) or the duration of dendritic cell stimulation
can also modulate the polarization of CD4+ T cells. Indeed, after prolonged
stimulation with LPS, IL-12 production in response to CD40L (or LPS) is
reduced. These exhausted dendritic cells prime mostly for Th2 and nonpo-
larized T cells expressing CCR7, also called central memory T cells (252).
tease inhibitor 9 (269) and SPI-6 (270), a serpin family member, that both
inhibit granzyme B, they can be eliminated by CTLs in vitro by the perforin-
dependent pathway (258) and in vivo (257) by perforin-independent un-
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known mechanisms (258). It is interesting that Th1 but not Th2 induces
SPI-6 expression in dendritic cells (270).
The analysis of the mechanisms underlying antigen presentation and T cell stim-
ulation provided the rationale for developing a novel strategy for immunotherapy,
based on the injection of antigen-pulsed dendritic cells. Several issues need to
be considered to ensure optimal outcome of dendritic cell-based vaccination pro-
tocols, including (a) a good manufacturing procedure used to expand dendritic
cells and (b) the source and formulation of antigen for appropriate peptide loading
on MHC molecules. These issues are still open, and only an extensive under-
standing of dendritic cell fundamental biology will allow us to develop effective
immunotherapy protocols. It is also important to consider, however, that this novel
immunotherapy approach is endowed with novel caveats and risks.
full-length antigens allows presentation of both MHC class I and II epitopes for any
MHC haplotype and the possibility to include sequences encoding immunomod-
ulators (6). The use of RNA, DNA, and substractive hybridization could allow for
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for patients bearing the appropriate MHC haplotypes, and were associated with
antigen and/or MHC class I loss variants in vivo (291, 292).
As mentioned in MHC Class I Restricted Antigen Presentation in Dendritic
Cells, apoptotic cells also allow efficient antigen loading in dendritic cells. Nouri-
Shirazi et al. (118) and Berard et al. (38) have shown that dendritic cells loaded with
killed allogeneic melanoma or prostate cells prime nave T cells to differentiate
into CTLs specific for a broad spectrum of shared tumor antigens and recognizing
naturally processed antigens.
We have shown that a novel tumor cell secretory compartment, exosomes, is a
defined source of shared rejection tumor antigens released in membrane vesicles
by living tumor cells. Tumor-derived exosomes contain whole native cytosolic
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and/or endosomal tumor antigens and constitutive hsps. Exosomes transfer tumor
antigen to dendritic cells and induce peptide-specific, MHC class Irestricted cross
presentation to T cell clones and in vitro tumor-specific CTL responses in patients
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lymphocytes (renal cell cancer and melanoma). Moreover, exosomes promote cross
protecting antitumor effects in both syngeneic and allogeneic mouse tumor models,
suggesting that they may transfer shared tumor antigens (120).
Human Trials
The first controlled evidence of the adjuvant role of mature dendritic cells in normal
volunteers was brought up in 1999/2000 by Steinmans group (296). While injec-
tion of unpulsed dendritic cells or antigen alone (KLH, TT, MP) failed to immunize,
priming of CD4+ T cells to KLH, boosting of TT specific T cell immunity, and
enhanced precursor frequency of MP-specific IFN- producing CTLs were shown
following injection of a single dose of mature dendritic cells. When T cells were
boosted in culture, there was an increase in MHC-specific tetramer-binding cells
and CTL after dendritic cell vaccination. Responses to all three antigens peaked at
3090 days after immunization and declined thereafter. Three volunteers were rein-
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jected with mature dendritic cells pulsed with matrix protein alone and displayed
a rapid boost in matrix protein-specific immunity (faster and greater magnitude of
CD8+ T cell specific responses), with direct cytolytic activity in one case.
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vitro and can stimulate nave T cells in vivo (C. Thery, L. Duban, P. Veron, O. Lantz,
S. Amigorena, et al., in preparation). Immature human dendritic cells also secrete
exosomes of similar protein composition and function (309). A good manufac-
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turing process has been engineered allowing scale up of exosome production and
purification with safety profile of the product in mice. A clinical trial has recently
been launched, aimed at vaccinating subcutaneously metastatic melanoma and
inoperable lung cancer patients with autologous dendritic cellderived exosomes
pulsed with Mage3 class I and II peptides.
Ideal vaccination processes should be cell free, off-shelf reagents, allow man-
ufacturing in large scale, and use immunorelevant tumor antigens regardless of
patient HLA haplotype. We are, obviously, far from this goal. In spite of encour-
aging preliminary clinical results in pilot studies and phase I/II trials (demonstrat-
ing feasibility and safety), dendritic cellbased immunotherapy awaits firm proof
of efficacy. In particular, correlations between enhanced specific CTL precursor
frequency and clinical responses have not been reported yet.
ACKNOWLEDGMENTS
P.G. was supported by Association pour la Recherche contre le Cancer, J.V. by
Ligue Nationale contre le Cancer, C.T. by Fondation pour la Recherche Medicale.
Due to space limitation, we could only cite a fraction of the published work, which
does not undermine the great value of uncited studies.
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P1: FRK
February 1, 2002 12:47 Annual Reviews AR152-FM
CONTENTS
FRONTISPIECE, Charles A. Janeway, Jr. xiv
A TRIP THROUGH MY LIFE WITH AN IMMUNOLOGICAL THEME,
Annu. Rev. Immunol. 2002.20:621-667. Downloaded from www.annualreviews.org
CONTENTS xi
INDEXES
Subject Index 887
Cumulative Index of Contributing Authors, Volumes 120 915
Cumulative Index of Chapter Titles, Volumes 120 925
ERRATA
An online log of corrections to Annual Review of Immunology
chapters (if any, 1997 to the present) may be found
at http://immunol.annualreviews.org/