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Kali
ski2,*
Departments of
*
Cell Biology and Histology and
Dermatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, at the moment of induction of
their maturation or shortly thereafter, to develop the capacity to
produce high levels of IL-12p70 upon subsequent contact with naive Th
cells. This effect is specific for IFN- and is not shared by other
IL-12-inducing factors. Type 1-polarized effector DC, matured in the
presence of IFN-, induce Th1 responses, in contrast to type
2-polarized DC matured in the presence of PGE2 that induce
Th2 responses. Type 1-polarized effector DC are resistant to further
modulation, which may facilitate their potential use in
immunotherapy. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) and Th2 cells (high producers of IL-4 and IL-5)
develop from a common pool of naive Th cells
(ThN)3 (1, 2). Depending on the character of the Ag and the route of its
entry, already 3 days after primary immunization, immune responses
induced in the same lymph nodes may show either the Th1 or the Th2
pattern, resulting in the production of different Ab isotypes (3, 4). Despite an abundance of data on the mechanisms governing Th
cell polarization, it is not entirely clear how such an early,
pathogen- and tissue-type dependent, polarizing signal can be delivered
from peripheral tissues to lymph node-based ThN. Although the commitment toward either the Th1 or the Th2 phenotype can be influenced by many signals active at the moment of ThN priming, the levels of IL-12p70 (IL-12) produced by APC are of major importance (1, 2). Dendritic cells (DC) are the professional APC for ThN, and thus for the initiation of primary immune responses (5, 6). They produce IL-12 upon interaction between CD40 on the APC and the rapidly induced CD40 ligand (CD40L, CD154) on the activated Th cell (7, 8, 9, 10).
The IL-12-producing capacity of DC is subject to regulation. Several
reports have shown that the ability of myeloid DC to produce IL-12 can
be stably suppressed by inflammatory mediators such as
PGE2 and IL-10, by glucocorticoids or
ß2 agonists, all resulting in DC populations
with enhanced Th2-promoting capacity (11, 12, 13, 14, 15). In
contrast, no studies have addressed the possibility to obtain
reciprocally modified myeloid DC with enhanced Th1-promoting capacity.
While numerous factors such as IFN-, LPS, CD40L, fixed bacteria,
bacterial DNA, and dsRNA can induce IL-12 production or up-regulate its
level when present at the site of DC-ThN interaction (9, 10, 16, 17, 18, 19), it remains unresolved whether high IL-12 production can
be also predetermined by the environmental factors immature DC meet in
peripheral tissues. Until now, no inflammatory mediators, or
pathogen-related products, have been identified that can induce stable
effector DC with an increased capacity to produce IL-12 upon a
subsequent encounter with ThN in the lymph nodes. The lack of such
studies can, at least partially, be explained by the view that human
myeloid DC are a Th1-promoting APC type per se, as judged by their
intrinsic ability to produce IL-12 upon activation (6).
This view was supported by a recent observation that human myeloid DC,
in contrast to human IL-3R+ plasmacytoid DC, can
induce the Th1 differentiation pattern in ThN (18).
However, that comparative study used an exogenous IL-12 inducer
(third-party CD40L-bearing cell line), leaving open the question of
whether the interaction of myeloid DC with ThN in neutral conditions
would still result in Th1 responses. Accepting the possibility that
myeloid DC may not be a Th1-driving APC population per se, in the
current study we addressed the question of whether immature DC can be
instructed to adopt such a function by environmental factors present at
the site of the induction of their maturation. We provide evidence
that, in contrast to various other IL-12-inducing factors, IFN- has
the unique capacity to prime DC for high IL-12 production and strong
Th1-promoting capacity.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Immature DC were generated from peripheral blood monocytes
(10) cultured in IMDM (Life Technologies, Paisley, U.K.)
containing 10% FCS (HyClone, Logan, UT), recombinant human (rh)GM-CSF
(500 U/ml; Schering-Plough, Uden, The Netherlands), and rhIL-4 (250
U/ml; Pharma Biotechnologie Hannover, Hannover, Germany)
(20). At day 6, the maturation of DC was induced by a
2-day exposure to either LPS (250 ng/ml; Difco, Detroit, MI) or a
combination of the cytokines rhIL-1ß (10 ng/ml, sp. act. 2 x
108 U/mg; Pharma Biotechnologie Hannover), and
rhTNF-
(50 ng/ml, sp. act. 1 x 108 U/mg;
Pharma Biotechnologie Hannover) (12, 20). Maturation was
induced in the absence or in the presence of IFN-
(103 U/ml, unless stated otherwise; a gift of Dr.
P. H. van der Meide, Biomedical Primate Research Center, Rijswijk,
The Netherlands), PGE2
(10-6 M, unless stated otherwise; Sigma, St.
Louis, MA), polyriboinosinic polyribocytidylic acid (poly I:C) (20
µg/ml; Sigma), soluble trimeric rhCD40L (sCD40LT) (1 µg/ml;
Immunex, Seattle, WA), or additionally by a combination of LPS and
IL-1ß/TNF-. Where indicated, DC were kept in nonmaturing
conditions during 2 days. All subsequent tests were performed after
harvesting the cells at day 8 and after removal of GM-CSF, IL-4,
IL-1ß, TNF-, LPS, IFN-, PGE2, poly I:C,
and sCD40LT by extensive washing.
Induction of IL-12p70 secretion by differentially matured DC
At day 8, DC were harvested, washed extensively (four times in
10 ml of culture medium), and 2 x 104
cells/well were stimulated in 96-well flat-bottom culture plates
(Costar, Cambridge, MA) in IMDM containing 10% FCS in a final volume
of 200 µl. The following stimuli were used: CD40L-transfected J558
cell line (J558-CD40L; a gift of Dr. P. Lane, University of Birmingham,
Birmingham, U.K.; 5 x 104 cells/200 µl),
which has been shown to induce IL-12p70 in an IFN--independent way
(7), or sCD40LT (1 µg/ml). DC stimulation was performed
in the absence or in the presence of either IFN-
(103 U/ml, unless stated otherwise) or
PGE2 (10-6 M).
Supernatants were harvested after 24 h, and the concentrations of
IL-12p70 were measured by ELISA (11). No IL-12p70
production was detected (detection limit 3 pg/ml) in any population of
unstimulated DC.
Isolation of CD4+ CD45RA+ CD45RO- ThN, cocultures with autologous DC, and induction of memory-type cytokines in maturing Th cells
ThN were isolated from peripheral blood leukocytes with the
negative selection human
CD4+/CD45RO- column kit
(R&D Systems, Minneapolis, MN). This method yielded highly purified
(>98%) CD4+ CD45RA+
CD45RO- ThN as assessed by flow cytometry (data
not shown). ThN (5 x 104 cells/200 µl)
were cocultured in 96-well flat-bottom culture plates (Costar) with
autologous DC (2 x 104 cells/200 µl)
matured under the influence of LPS or of LPS in the presence of either
IFN- (103 U/ml) or PGE2
(10-6 M) and coated with superantigen
(Staphylococcus aureus enterotoxin B; SEB) (1 ng/ml; Sigma).
Where indicated, IFN- (103 U/ml) was added to
the cocultures. Culture supernatants were harvested after 24 h,
and the concentrations of IL-12p70 were measured by ELISA.
Alternatively, T cells were allowed to expand for 14 days. On day 5,
IL-2 (10 U/ml; Cetus, Emeryville, CA) was added and the cultures were
further expanded for another 9 days. On day 14, resting memory Th
cells were harvested, washed, and restimulated with CD3 mAb
(CLB-T3/3; Central Laboratory of the Netherlands, Amsterdam, The
Netherlands) and CD28 mAb (CLB-CD28/1; Red Cross Blood Transfusion
Service) (11). The concentrations of IFN- and IL-4 in
24-h supernatants were measured by ELISA (detection limit 100 pg/ml and
60 pg/ml, respectively) (11).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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instructs maturing myeloid DC to produce enhanced levels of
IL-12 upon subsequent stimulation
To analyze whether DC can be instructed to adopt an enhanced
Th1-promoting capacity, myeloid DC were induced to mature by LPS or by
a combination of inflammatory cytokines (IL-1ß plus TNF-) either
in the absence or in the presence of IFN-. IFN- profoundly
increased the ability of maturing DC to produce IL-12 upon subsequent
stimulation in the absence of IFN- with either J558-CD40L (Fig. 1
A) or sCD40LT (Fig. 1B). This effect was observed irrespectively of the mode of
induction of DC maturation. Although several immune mediators and
pathogen-derived products are able to induce or up-regulate IL-12
production (9, 10, 16, 17, 19), the IL-12-priming effect
of IFN- appeared to be unique. None of the other IL-12-inducing
factors, i.e., LPS, synthetic dsRNA poly I:C, or sCD40LT could replace
IFN- in priming DC for enhanced IL-12 production upon subsequent
CD40L activation (Fig. 1, A and B).
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did not affect the maturation-associated phenotypical changes,
neither elevating nor inhibiting the expression of the mature DC marker
CD83, the costimulatory molecules CD40, CD80, and CD86, and the class
II MHC Ag-presenting molecule HLA-DR (data not shown).
The IL-12-priming effect of IFN- was dose dependent and evident even
at concentrations as low as 1 U/ml (Fig. 2A), suggesting that locally
produced IFN- in peripheral tissues, e.g., produced by rapidly
recruited NK cells at the site of viral infections (21),
can instruct migrating DC to secrete increased levels of IL-12 upon
subsequent activation in the lymph nodes. In accord with previous
observations (11), in sharp contrast to IFN-, the
presence of PGE2 during maturation of DC
dose-dependently suppressed their ability to secrete IL-12. IFN- and
PGE2 reciprocally regulated the capacity of
maturing DC to secrete IL-12, without any clear dominance of either
factor. These results suggest that the actual IL-12-producing capacity
of DC originating from particular environments reflects the ratio of
IFN- to PGE2 concentrations (possibly being
influenced also by other factors present locally).
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was maximal when IFN- was added
at the moment of induction of DC maturation (Fig. 2
B). It
was strongly pronounced if IFN- was added within the first 2 h
after the induction of maturation, but still clearly visible if IFN-
addition was delayed for 12 h. This indicates that the capacity of
mature DC to secrete IL-12 upon subsequent encounter with ThN is
determined mainly by the conditions present at the site of induction of
DC maturation. As expected (9, 10, 11), the presence of
exogenous IFN- during the CD40L-mediated stimulation of mature DC
was a prerequisite for high-level IL-12 production by control mature DC
(Fig. 2C, open bars). In contrast, DC matured in the
presence of IFN- (Fig. 2C, filled bars) acquired the
capacity to produce large amounts of IL-12, even in the absence of
IFN- during their subsequent stimulation. Moreover, although control
DC dose-dependently responded to IFN- when added at the moment of
stimulation, the levels of IL-12 produced by these DC never reached
those produced by IFN--preexposed DC, remaining at least 10-fold
lower. These results are consistent with the decreased responsiveness
of mature DC to IFN- and their reduced expression of the IFN-R
(20). These observations indicate that high-level IL-12
production by mature DC depends mainly on the presence of IFN- at an
earlier stage, i.e., during the induction of their maturation, rather
than on the presence of IFN- during their subsequent
stimulation. Type 1- and type 2-polarized myeloid effector DC induce different Th cell responses
To test whether the presence of IFN- during the maturation of
DC instructs them to adopt a Th1-inducing function, we used a
superantigen model (9, 10, 11, 20) that, similar to TCR
transgenic animal models (22), allows a significant
proportion of human Th cells to be activated by APC and to induce early
IL-12 production in a CD40L-dependent mechanism (9, 11).
As expected (9, 10), the induction of detectable IL-12
production in control DC by ThN required the additional presence of
exogenous IFN- (Fig. 3A,
crosshatched bar). In contrast, the interaction of ThN with DC exposed
to IFN- during maturation (Fig. 3A, filled bar) resulted
in substantial IL-12 production independently of any additions. DC
matured under neutral conditions and DC exposed to IFN- or
PGE2 during maturation all expressed similar
levels of HLA-DR and costimulatory molecules and induced similar
proliferation in responding ThN, resulting in a similar Th cell yield
(data not shown and Ref. 11). However, while the priming
of ThN with control DC induced memory Th0-type cells, secreting
moderate levels of both IFN- and IL-4 after restimulation (Fig. 3B, circles), DC exposed to IFN- induced a strong bias
toward Th1 (Fig. 3B, squares). Conversely, DC exposed to
PGE2 promoted a Th2 pattern of differentiation in
ThN (Fig. 3B, diamonds). In summary, these data demonstrate
that the presence of a different set of immune mediators at the site of
the induction of DC maturation can instruct maturing DC to adopt
reciprocal Th1- vs Th2-inducing functional phenotypes.
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The current observations indicate that mediators of nonspecific
immunity, such as a product of activated NK cells, IFN-
(21), and a common inflammatory mediator,
PGE2, can modulate the production of IL-12 in DC
in two different fashions (Fig. 4).
First, they can directly modulate the levels of IL-12 produced by
sentinel-type immature DC in peripheral tissues (Fig. 4A).
Probably more important, however, the presence of these mediators at
the site of activation of immature DC can drive their maturation toward
Th1- or Th2-promoting effector DC types that cannot be repolarized at a
later time point. Type 1 effector DC, matured in the presence of
IFN-, produce high levels of IL-12 upon subsequent CD40 triggering.
This high-level IL-12 production does not depend on the presence of
IFN- at this stage and can no longer be suppressed by
PGE2 (Fig. 4B). On the other hand,
type 2 effector DC, matured in the presence of
PGE2 (Fig. 4C), are deficient in IL-12
production. Also this type of effector DC is stable and resistant to
repolarization by IFN-. In addition, the differences in
IL-12-producing capacities established during the maturation are
relatively stable in time (up to 24 h, data not shown and 11). The possibility to obtain stable type 1-promoting effector DC has
interesting clinical implications. Such cells may be candidates for
Ag-specific induction of therapeutic Th1 responses in cancer and in
chronic infections with intracellular pathogens.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The current data indicate that neither a Th1- nor a Th2-inducing capacity is an intrinsic feature of myeloid DC. Both capacities can be acquired by uncommitted immature DC in response to signals delivered by the local microenvironment.
The ability of an individual DC to respond in a flexible fashion to
different microenvironments opens the possibility that the tuning of Th
cell responses to the type of pathogen and invaded tissue can benefit
from the adaptation of DC function to the conditions they encounter in
the pathogen-invaded tissue. This hypothesis is supported by an
increasing amount of data obtained in vivo. Freshly isolated airway DC
and Peyer’s patches DC, as opposed to spleen DC, display a
Th2-promoting capacity (26, 27, 28, 29). These differences can be
observed despite similar frequencies of myeloid DC in Peyer’s patches
and spleen DC populations (29), suggesting a role for
tissue-specific DC polarization. Several DC-polarizing factors have
been identified, which may be differentially produced in distinct
tissues, and the production of which can be differentially regulated by
different pathogens. IFN-, produced by NK cells during viral
infections (21), and probably other as yet unknown
factors, may contribute to the development of type 1-polarized DC.
Although many other factors, including viral and bacterial products
(e.g., dsRNA, bacterial DNA, fixed bacteria, and LPS) may induce or
enhance IL-12 production when present at the moment of DC-T cell
interaction (9, 10, 16, 17, 19), none of these factors
shares the unique capacity of IFN- to induce stably polarized
effector DC with enhanced IL-12-producing capacity. In contrast, many
more factors have been identified that can stably suppress the
IL-12-producing capacity of DC. Agents with a cAMP-elevating potential,
such as PGE2, ß2
agonists, and possibly histamine, that inhibit the IL-12-producing
capacity of DC (11, 15, 30) and enhance their
immunostimulatory function (11), represent a potentially
larger group of type 2 DC-polarizing factors. Another set of factors,
including IL-10 and glucocorticoids, induces the DC that are similarly
IL-12-deficient (11, 12, 13, 14, 31), but also have reduced
stimulatory capacity (11). This latter type of DC was
reported to induce tolerance in ThN (32), while in other
models it promotes the induction of Th2-type responses (12, 31). It is noteworthy that tissue environments with high
concentrations of IL-10, PGE2, or TGF-ß have
been described in the body compartments and several disease states
associated with Th2 responses, e.g., the anterior chamber of the
eye, certain tumors, chronic disease states, and UV- irradiated
skin.
It has been proposed that tissue-derived signals instruct the immune system to initiate immune responses (33). The present data implicate that tissue-derived signals, carried by DC, can also determine the initial polarization of ThN responses and, hence, the class of the initiated response. In this model, migrating DC, apart from carrying antigenic and costimulatory signals ("signal one" and "signal two"), are further equipped with the capacity to transmit a third type of signal that reflects both the nature of the pathogen and of the invaded tissue. This additional signal may allow for a rapid selection of the most appropriate effector mechanisms of immunity, contributing to the effectiveness of the response and reducing the risk of collateral damage to own tissues.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Drs. M. L. Kapsenberg or P. Kaliski, Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands.
3 Abbreviations used in this paper: ThN, naive Th cells; DC, dendritic cells; CD40L, CD40 ligand (CD154); poly(I:C), polyriboinosinic polyribocytidylic acid; J558-CD40L, CD40L-transfected J558 cell line; sCD40LT, soluble trimeric human recombinant CD40L; SEB, Staphylococcus aureus enterotoxin B; rh, recombinant human.
Received for publication October 6, 1999. Accepted for publication February 16, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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5% of the mean), are from one representative experiment of
three. B, Maturation of DC was induced by LPS at day 6
(t = 0 h). Either IFN-
) or in
the presence of IFN-
). Alternatively, ThN were cocultured (in
the absence of IFN-
). No IL-12p70 was produced in the absence of
either ThN or SEB. IL-12p70 concentrations in 24-h supernatants were
determined by ELISA. Results, expressed as mean ± SD of
triplicate cultures, are from one representative experiment of three.
B, ThN were primed in the presence of SEB by DC matured
with LPS under neutral conditions (•) or with DC matured with LPS in
the presence of either 103 U/ml of IFN-
). Th cells were
restimulated on day 14 with anti-CD3 mAb and anti-CD28 mAb, and
the concentrations of IFN-