By
From the * Département de Biologie Moléculaire, Université Libre de Bruxelles, B-1640
Rhode-Saint-Genèse, Belgium; Veterinary and Agrochemical Research Center, B-1180 Brussels, Belgium;
and § Laboratorium of Hematologie-Immunologie, Vrije Universiteit Brussel, B-1090 Brussels, Belgium
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Abstract |
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Cells of the dendritic family display some unique properties that confer to them the capacity to
sensitize naive T cells in vitro and in vivo. In the mouse, two subclasses of dendritic cells (DCs)
have been described that differ by their CD8 expression and their localization in lymphoid
organs. The physiologic function of both cell populations remains obscure. Studies conducted
in vitro have suggested that CD8
+ DCs could play a role in the regulation of immune responses, whereas conventional CD8
DCs would be more stimulatory. We report here that
both subclasses of DCs efficiently prime antigen-specific T cells in vivo, and direct the development of distinct T helper (Th) populations. Antigen-pulsed CD8
+ and CD8
DCs are
separated after overnight culture in recombinant granulocyte/macrophage colony-stimulating
factor and injected into the footpads of syngeneic mice. Administration of CD8
DCs induces a Th2-type response, whereas injection of CD8
+ DCs leads to Th1 differentiation. We
further show that interleukin 12 plays a critical role in Th1 development by CD8
+ DCs.
These findings suggest that the nature of the DC that presents the antigen to naive T cells may
dictate the class selection of the adaptative immune response.
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Introduction |
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Since their discovery 25 years ago, dendritic cells (DCs)1
have gained increasing interest from immunologists, as
they are specialized in the capture, processing, and transport of the antigen to lymphoid organs where they probably sensitize antigen-specific naive T lymphocytes (1).
More recently, Shortman and colleagues developed a procedure that incorporated a step to dissociate DC-lymphocyte complexes, leading to the discovery of a new subset of
DCs that expresses a CD8 homodimer and limits the
proliferation of CD4+ T cells in vitro by Fas-mediated
death (2, 3). Based on these observations and on a recent
report that T cell area DCs express high levels of self-peptides (4), it was suggested that the CD8
+ cells could play a
role in peripheral tolerance in vivo, whereas conventional
CD8
DCs would initiate immune responses. This hypothesis was challenged by recent reports that IL-12 was
produced by CD8
+ rather than CD8
DCs (see below).
This prompted us to assess the function of both subclasses
in vivo by injecting purified DCs, pulsed extracorporeally with antigen, into the footpads of syngeneic mice and analyzing the immune response of LN cells.
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Materials and Methods |
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Mice.
Balb/c mice were purchased from Iffa-Credo. Balb/c IL-12 p40Purification and Stimulation of DCs.
DCs were purified as shown previously (6), except that spleen cells were digested with collagenase, further dissociated in Ca2+-free media in the presence of EDTA, separated into low- and high-density fractions on a Nycodenz gradient, and cultured overnight with 15 ng/ml rmGM-CSF, as described (3). DCs were pulsed with antigen (30 µg/ml KLH) during overnight culture (6). The CD8Induction of IL-12 from DC Subsets.
Low-density spleen cells (see above) were enriched for CD11c expression and further separated according to CD8Immunization Protocol.
Antigen-pulsed DCs were washed in RPMI 1640 and administered at a dose of 3 × 105 cells into the hind footpads, according to a protocol described by Inaba et al. (9). When indicated, some groups of animals were treated with 1 mg anti-CD4 mAbs (GK 1.5), to selectively deplete CD4+ T cell subset in vivo, as described previously (10). Some mice were injected daily with 0.2 µg i.p. rmIL-12 on days 0, 1, 2, and 3. Draining popliteal LNs were harvested 5 d after DC injection.In Vitro Assays.
LN cells were cultured in Click's medium supplemented with 0.5% heat-inactivated mouse serum and additives. The proliferation was measured as thymidine incorporation during the last 16 h of a 4-d culture. Culture supernatants were assayed for IL-2 after 24-48 h, and for IFN- ![]() |
Results |
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DCs were purified from spleens,
pulsed with KLH during overnight culture (6), and further
separated according to CD8 expression by FACS® sorting
or by positive/negative selection on MACS®. Reanalysis of
the sorted cell populations confirmed purity >99% (FACS®)
or 97% (MACS®). 3 × 105 DCs were injected into the
hind footpads of syngeneic mice, and the popliteal LNs
were harvested 5 d later. The data in Fig. 1 a indicate that
administration of purified CD8
+ or CD8
DCs, or
both, loaded ex vivo with antigen, resulted in T cell priming, as assessed by KLH-dependent proliferation in culture. The proliferative response of LN cells from mice injected
with CD8
+ DCs was consistently higher compared with
animals primed with CD8
DCs. T cell priming was prevented by treatment of mice with neutralizing anti-CD4
mAbs, showing that the KLH-specific response was dependent on CD4+ T lymphocytes.
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We next analyzed the cytokines (12) released
by LN cells from mice primed with either subset in vivo.
The data in Fig. 1 indicate that the subclasses of DCs have
the potential to differentially skew cytokine production towards Th1 and Th2 tendencies (12): CD8 DCs induced
the activation of cells secreting high levels of IL-4, IL-5,
and IL-10 and low levels of IL-2 and IFN-
, whereas CD8
+ DCs sensitized cells producing IL-2 and IFN-
,
but little IL-4, IL-5, and IL-10. Unseparated splenic DCs
(11; and data not shown) or a combination of both subsets
(at a proportion of 1 CD8
+ to 10 CD8
) induced the
activation of helper cells secreting a large array of lymphokines.
These results indicate
that both CD8+ and CD8
subsets of DCs can act as
adjuvant of the immune response and differentially regulate
the development of CD4+ Th cells. As in vitro data suggested that CD8
+ DCs could kill Fas-expressing cells (3),
T lymphocytes may undergo Fas-mediated apoptosis once
they are activated, i.e., later during the primary response.
Therefore, we tested whether an anamnestic response was
developed. Unseparated, KLH-pulsed DCs were injected
into the hind footpads of mice that were untreated or immunized 14 d earlier with various DC populations. LN
cells were harvested 2 d later and cultured with or without
antigen. The data in Fig. 2 a indicate that a memory response was induced in all preimmunized groups, as assessed
by antigen-specific T cell proliferation of LN cells from
mice that received two injections of DCs, but not in
groups that received only one injection. Of note, the cytokine profiles were determined by the subclass of DCs
used to prime animals: mice injected with CD8
+ or
CD8
DCs and boosted with unseparated DCs displayed
a secondary response of Th1 and Th2 type, respectively
(Fig. 2). These findings indicate that both DC subsets induce the development of memory helper cells that upon
recall with the same antigen differentiate into distinct helper populations.
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There is evidence that the maturation of
Th precursors into biased Th1 or Th2 populations is
strongly influenced by cytokines in the environment (13).
In particular, IL-12 appears as the dominant cytokine driving the differentiation of Th1 lymphocytes in vitro and in
vivo (14, 15). We found that CD8+ DCs produced high
levels of IL-12 heterodimer upon stimulation, whereas
CD8
DCs secreted little if any IL-12 (Table I). The role
of IL-12 in Th1 priming was further documented by the
observation that CD8
+ DCs isolated from mice deficient
for IL-12 (5) induced little IFN-
and intermediate levels
of IL-4 when injected into syngeneic mice, compared with
CD8
+ DCs from wild-type mice (Fig. 3, a and b). Conversely, coinjection of rIL-12 and antigen-pulsed CD8
DCs resulted in the development of a polarized Th1-type
immune response (Fig. 3, c and d).
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Discussion |
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There is increasing evidence that protection against parasites or infectious diseases relies on the character of the immune response, i.e., the Th1/Th2 balance. In particular,
Th1 cells are important effectors involved in the eradication of intracellular infectious pathogens, whereas Th2
lymphocytes are efficient to eliminate extracellular parasites. Importantly, the development of the inappropriate Th
subset not only fails to eradicate the pathogen but can cause
immunopathology (for a review, see reference 13). Therefore, it is of major interest to identify the factors that influence the differentiation of distinct Th cell subsets in vivo.
We show herein that two subclasses of DCs differentially regulate the development of Th cells secreting discrete sets
of lymphokines: CD8+ DCs direct the differentiation of
Th1 cells, whereas CD8
DCs induce Th2-type responses
in vivo. We further show that both DC subclasses induce
memory responses, and that the activation of Th1 responses
by CD8
+ DCs correlates with their production of IL-12
p70 heterodimer.
Our data are in agreement with recent reports that
CD8+ DCs are the source of IL-12. In Flt3 ligand-treated
mice, a DC subset containing a majority of CD8
+ cells
was shown to secrete very high levels of IL-12 (16). Similarly, most DCs exposed to soluble Toxoplasma gondii
tachyzoite extract in vivo that stained for IL-12 p40 were
shown to belong to the CD8
subset (17). In addition, our
results suggest that the same cells, i.e., the transferred DCs,
function as APCs and IL-12-producing cells, as DCs from
p40 knockout mice have lost the capacity to induce a Th1-type response in a wild-type host. These observations and
other studies suggest that IL-12 is a dominant factor in directing the development of Th1 cells producing high levels
of IFN-
in vitro and in vivo, although other factors may affect Th subset development (13). Of note, several reports suggest that IL-12 production by DCs requires their prior
activation and that the amount of IL-12 depends on the
mode of activation. Reis e Sousa and collaborators reported
a CD40L- and IFN-
-independent production of IL-12
after infection with T. gondii or injection of LPS (17). Koch
et al. (18) found that ligation of CD40 and MHC class II
molecules independently triggered IL-12 production by
murine DCs. Similarly, CD40L was found to be the most
effective stimulus to induce IL-12 by DCs generated from
human peripheral blood monocytes (19). Therefore, it is
tempting to speculate that, in our model, the transferred
antigen-pulsed DCs are triggered to release IL-12 upon antigen-specific interaction with T lymphocytes in vivo. Experiments are underway to define the role of CD40- CD154 interaction in Th1 priming and to compare the
IL-12 produced by DCs at various stages of maturation.
There is some evidence that CD8+ and CD8
DCs
belong to distinct lineages. Shortman and colleagues have
found in intravenous transfer studies that CD8
serves as a
marker of the DC progeny of the low CD4 precursor, in
both the thymus and the spleen of irradiated recipients,
thereby suggesting that CD8
+ DCs are of lymphoid origin (20, 21). Conversely, the CD8
DCs would be of
myeloid origin, as they are relatives of monocytes and macrophages and are GM-CSF dependent (21, 7). Both classes of DCs maintain their CD8
or CD8
+ status in culture
in the presence of GM-CSF, and therefore appear as stable
distinct lineages (7). Of note, CD8
remained a stable marker on DCs cultured for 5 d in the presence of GM-CSF, IFN-
, and/or activated T cells (our unpublished observations).
A recent study by Pulendran et al. (21a) confirmed that
both subsets of DC differentially regulated the development of T helper cells in vivo. They showed that the lymphoid-related subsets induced high levels of IFN- and IL-2,
but little Th2 cytokines, whereas the myeloid-related subset induced large amounts of IL-4 and IL-10, in addition to
IFN-
and IL-2. The CD8
+ population used in the
present study is CD11c+CD11bdull or
, and therefore is
likely to represent the lymphoid-related population D/E
described by Pulendran and colleagues (16). By contrast, the CD8
DCs are CD11c+CD11b+ and resemble the
myeloid-related DC subset referred to as population C
(data not shown). The distinct regulation of the IFN-
and
IL-2 synthesis, compared with our study, could be related
to differences in the purification procedures, in the maturation state of the DCs transferred (fresh versus cultured
DCs), in the form of antigen (peptide versus protein), and/or
in the precursor frequency of antigen-reactive T cells
(TCR transgenic versus wild-type mice). It is noteworthy
that injection of CD8
+ and CD8
DCs isolated from
mice treated with Flt3 ligand (provided by Dr. C. Maliszewski, Immunex, Seattle, WA) induced the development of
similar Th cells compared with DCs purified from untreated mice, suggesting that administration of Flt3 ligand
did not alter DC function (data not shown).
Two reports have shown that the cell population containing the highest proportion of CD8+ cells was consistently less efficient at stimulating the proliferation of antigen-specific cells in vitro (3, 22). A ligand for Fas was
demonstrated on the surface of CD8
+ but not CD8
DCs, and the suboptimal activation of T cells by CD8
+
DCs was associated with marked T cell apoptosis via Fas
engagement (3). We show here that injection of pulsed
CD8
+ and CD8
DCs induced equally strong T cell
proliferative responses upon in vitro restimulation. Although we did not measure the expansion of T cells in situ,
a difference between the in vitro and in vivo function of
CD8
+ DCs could be due to the segregation of cell populations into distinct geographic compartments in vivo after
T cell activation (23) compared with the confined microenvironment in culture plates. Alternatively, it is possible that Th1-type responses, which could be deleterious,
are controlled by a feedback mechanism involving Fas-
mediated killing of T lymphocytes once activated (24, 25). Interestingly, there is evidence that CD95L may be a mediator of costimulation and inflammation as well as a death agonist (26): CD95L has been shown to recruit neutrophils and activate their cytotoxic machinery, leading to local inflammation (29). As inflammatory products seem to
induce the maturation of DCs and their migration to lymphoid tissues (31, 32), inflammation may be crucial for the
initiation of immunity. Experiments are underway to test
whether FasL expression by CD8
+ is required for the induction of a Th1-type response in vivo.
It is intriguing that CD8+ and CD8
DCs seem to be
located in distinct microenvironments of the spleen (16). In
Balb/c mice, a majority of CD8
DCs reside at the margin between the red and white pulp, whereas most CD8
+
DCs are present in the zones where T cells are located (our
unpublished observations). Injection of LPS results in the
redistribution (32) of both subsets into the T cell area (our
unpublished observations), suggesting that both subsets
have migratory properties. It is notable that CD8
+ DCs
express high levels of DEC-205, a multilectin-like receptor (33) which could be specific for carbohydrates that are
common constituents of microbial cell walls. In addition,
the expression of CD1d, an MHC-like molecule which
presents antigens mainly derived from prokaryotes (34), has
been shown to be highest on the CD8
+ DC subset (16).
Therefore, it is tempting to speculate that the CD8
+ subset of DCs preferentially capture and present microbial antigens and elicit a Th1-type response.
In conclusion, two subsets of DCs, which differ by phenotype, functional, and histologic parameters, exist in the
mouse, each one initiating a different class of response in
vivo and thereby stimulating different effector mechanisms.
Our data show that CD8+ DCs drive the development of
Th1-type immune responses, whereas CD8
DCs induce
the differentiation of Th2-type responses. These observations predict that CD8
+ DCs might not be exploited to
induce tolerance in vivo and confer immune privilege to
grafts, but instead may be attractive for eliciting therapeutic
antitumor immunity.
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Footnotes |
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Address correspondence to Muriel Moser, Laboratoire de Physiologie Animale, Université Libre de Bruxelles, Rue des Chevaux, B-1640 Rhode-Saint-Genèse, Belgium. Phone: 32-2-650-98-50; Fax: 32-2-650-98-40; E-mail: mmoser{at}dbm.ulb.ac.be
Received for publication 18 September 1998 and in revised form 18 November 1998.
The Laboratory of Animal Physiology was supported by grants of the Fonds National de la Recherche Scientifique/Télévie, by the Fonds de la Recherche Fondamentale Collective, by the European Commission (CEC TMR Network Contract FMRX-CT96-0053), and by the Belgian Programme on Interuniversity Poles of Attraction initiated by the Belgian State, Prime Minister's Office, Science Policy Programming. R. Maldonado, T. De Smedt, and M. Moser are supported by the Fonds National de la Recherche Scientifique.We thank Dr. K. Shortman for interesting discussions; Drs. B. Pulendran and C. Maliszewski for sharing unpublished results and for useful comments; Dr. M. Goldman for careful review of the manuscript; Dr. J. Magram for providing IL-12-deficient mice; and G. Dewasme, M. Swaenepoel, F. Tielemans, and P. Veirman for technical assistance.
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