| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
and to Bacterial IL-12 Inducers: Decreased Ability of Mature Dendritic Cells to Produce IL-12 During the Interaction with Th Cells1
Kali
ski2Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-induced maturation to produce the major
Th1-driving factor IL-12. DC at the early stages of maturation (2 and
4 h) produced elevated amounts of IL-12 p70 during interaction
with CD40 ligand-bearing Th cells or, after stimulation with the T
cell-replacing factors, soluble CD40 ligand and IFN-
. The ability to
produce IL-12 was strongly down-regulated at later time points, 12
h after the induction of DC maturation, and in fully mature
CD83+ cells, at 48 h. In contrast, the ability of
mature DC to produce IL-6 was preserved or even enhanced, indicating
their intact responsiveness to CD40 triggering. A reduced
IL-12-producing capacity of mature DC resulted mainly from their
impaired responsiveness to IFN-, a cofactor in CD40-induced IL-12
p70 production. This correlated with reduced expression of IFN-R
(CD119) by mature DC. In addition, while immature DC produced IL-12 and
IL-6 after stimulation with LPS or Staphylococcus aureusCowan I strain, mature DC became unresponsive to these
bacterial stimuli. Together with the previously described ability of
IL-10 and PGE2 to stably down-regulate the ability to
produce IL-12 in maturing, but not in fully mature, DC, the current
data indicate a general resistance of mature DC to IL-12-modulating
factors. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
production and
increased susceptibility to intracellular pathogens, documented a
similar role for IL-12 in humans.
IL-12 is a product of several types of APC, including dendritic cells
(DC)3, 1, 6, 7, 8 . DC produce
IL-12 in response to exogenous stimuli, e.g., bacteria and their
products, such as Staphylococcus aureus Cowan I
strain (SAC) and LPS 9, 10, 11, 12 . In addition, IL-12 production can
be induced by CD40 ligation 7, 8, 9, 10, 13 . While CD40 triggering alone is
sufficient to induce the production of the p40 subunit of IL-12 13 ,
the optimal induction of bioactive IL-12 p70 heterodimer requires
either very high levels of CD40 cross-linking, e.g., provided by CD40
ligand (CD40L)-transfected J558 cells 7 , or additional signals, which
may be provided by IFN- or bacterial LPS 9, 10, 13 . The
combination of CD40L and IFN- represents an endogenous pathway of
IL-12 induction that operates during the interaction of CD40-bearing DC
with CD40L-expressing Th cells 9, 13 .
Depending on their maturation stage and their localization, DC perform
different functions within the immune system. Immature
CD83- DC residing in peripheral tissues are poor
stimulators of primary T cell responses. Instead, they act as immune
sentinels by virtue of their ability to collect information about
invading pathogens and carry it to the draining lymph nodes. Activation
of immature DC directly by a pathogen or indirectly by the
pathogen-induced cytokines, such as IL-1ß and TNF- 14, 15, 16 ,
results in the up-regulation of their stimulatory capacity and the
migration to lymph nodes. Depending on the type of tissue in which they
reside and the character of the pathogen-related migration-inducing
signals, DC reach the lymph nodes within 4–48 h 17, 18, 19, 20, 21 . Here, mature
CD83+ DC act as effective inducers of primary responses of
Ag-specific naive Th cells 14, 15, 16 .
In addition to this role of DC as the initiators of immune responses, tissue-type DC perform an important function during the effector phase of immune responses, acting as APC for peripheral tissue-homing memory T cells 14, 22 .
Since in either of these two situations the induction of IL-12 occurs in different conditions and can serve different populations of responding cells (naive Th cells in lymph nodes vs effector cells in peripheral nonlymphoid tissues, such as primed Th cells, NK cells, and CD8+ CTLs), we analyzed the requirements for the effective IL-12 induction in immature and mature monocyte-derived human CD1+ DC 23 and compared the levels of IL-12 production in either DC population.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
All cultures were performed in Iscove’s modified Dulbecco’s
medium with 10% FCS (HyClone, Logan, UT). The following mAb were used:
CD1a (OKT6; Ortho, Beerse, Belgium), HLA-DR (L243; Becton Dickinson,
San Jose, CA), CD83 (HB15; Immunotech, Marseille, France), CD115 (GR12;
Oncogene, Cambridge, MA), CD80 and CD86 (B7-24 and 1G10; both provided
by Innogenetics (Ghent, Belgium), CD40 (EA-5; a gift from Dr. T.
LeBien, University of Minnesota, Minneapolis, MN), and CD119 (IFN-R
-chain, BB1E2; provided by InstruChemie, Hilversum, The
Netherlands). The following isotype-matched control mAbs were used:
MOPC-21, UPC-10, and MOPC-141 (respectively, IgG1, IgG2a, and IgG2b;
all obtained from Sigma, St.Louis, MO). The mAb-labeled cells were
analyzed using FACScan (Becton Dickinson), after application of
FITC-coupled goat F(ab')2 anti-mouse IgG and IgM
(Jackson ImmunoResearch Laboratories, West Grove, PA) as a
secondary reagent.
Isolation of monocytes and CD4+ Th cells
Monocytes and lymphocytes were isolated from peripheral blood of healthy volunteers as described previously 10 . CD4+ Th cells were isolated from the lymphocyte fraction using CD4-specific Dynabeads/Detatchabead system (Dynal, Oslo, Norway), accordingly to the manufacturer’s instructions.
Generation of immature CD1a+CD83- DC and induction of their final maturation
A procedure of Sallusto 23 was used. Monocytes were cultured
in the presence of recombinant human granulocyte-macrophage CSF (500
U/ml; a gift from Schering-Plough, Uden, The Netherlands) and
recombinant human IL-4 (250 U/ml; PBH, Hannover, Germany). On day 6 the
cultures consisted of uniformly HLA-DR+,
CD83-CD115+ immature DC, without any
detectable CD3+ cells. Over 90% of the cells expressed
high levels of CD1a. To induce final maturation, recombinant human
IL-1ß (10 ng/ml, corresponding to 5 x 102 U/ml;
Boehringer Mannheim, Germany) and recombinant human TNF- (50 ng/ml,
corresponding to 5 x 103 U/ml; PBH) or LPS (100
ng/ml; Difco, Detroit, MI) were added at the indicated time points,
2–48 h before harvesting the cells. On day 8 DC were harvested; washed
four times (each time in 10 ml of fresh medium) to remove IL-1ß,
TNF-, LPS, granulocyte-macrophage CSF, and IL-4; and subsequently
used for cocultures with Th cells or stimulated as indicated.
Cocultures of DC with CD4+ Th cells and DC stimulation
Freshly isolated CD4+ T cells (6 x
104) were cocultured with DC (2 x 104) at
different stages of maturation in a final volume of 200 µl in the
presence of superantigen (1 ng/ml staphylococcal enterotoxin B
(SEB); Serva, Heidelberg, Germany). Supernatants were harvested after
24 h of coculture. Alternatively, DC at different time points
after the induction of their maturation (2 x 104
cells in 200 µl) were stimulated for 24 h with one of the
following stimuli: soluble recombinant CD40L 24 (1 µg/ml; a
gift from Immunex, Seattle, WA) in combination with recombinant human
IFN- (1000 U/ml; a gift from Dr. P. H. van der Meide,
Biomedical Primate Research Center, Rijswijk, The Netherlands);
CD40L-transfected J558 plasmocytoma cells (J558-CD40L; 5 x
104 cells/well; a gift from Dr. P. Lane, Birmingham, U.K.),
which were previously shown to induce IL-12 p70 in an
IFN--independent manner 7 ; SAC (75 µg/ml; Calbiochem, San Diego,
CA); or LPS (100 ng/ml; Difco). The concentrations of cytokines in 24-h
supernatants were analyzed with specific solid phase sandwich ELISAs.
Cytokine measurements
An IFN- ELISA (sensitivity, 100 pg/ml) 25 was performed
using a pair of specific mAb, MD2 and MD1, both gifts from Dr. P. van
der Meide (Biomedical Primate Research Center). The IL-4 ELISA
(sensitivity, 50 pg/ml) 26 was performed using a pair of specific
mAb, CLB-IL-4/5 and CLB-IL-4/1 (both obtained from CLB, Amsterdam, The
Netherlands). The IL-5 ELISA (sensitivity, 10 pg/ml) was performed
using a specific TRFK5 mAb (a gift from Dr. H. Savelkoul, Erasmus
University, Rotterdam, The Netherlands) and JES1-5A10 mAb (PharMingen,
San Diego CA). The IL-12 p70 ELISA (sensitivity, 3 pg/ml) 27 was
performed using p70-specific mAb 20C2 (a gift from Dr. M. K.
Gately, Hoffmann-La Roche, Nutley, NJ) and p40-specific C8.6 mAb (a
gift from Dr. G. Trinchieri, The Wistar Institute, Philadelphia, PA).
Concentrations of IL-6 in 24-h supernatants were measured by specific
IL-6 ELISA (sensitivity, 20 pg/ml), using a pair of anti-IL-6 mAb,
58.126.08 and biotinylated 58.126.02, both obtained from Medgenix
(Fleurus, Belgium).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The exposure of monocyte-derived
CD1a+CD83- immature DC 10, 28 to the
inflammatory cytokines IL-1ß (5 x 102 U/ml) and
TNF- (5 x 103 U/ml) resulted in the initiation of
their final maturation. This was evidenced by a rapid appearance of
CD83 and the up-regulation of surface expression of CD40, CD80 (B7.1),
and particularly CD86 (B7.2; Fig. 1
). To
test whether DC at different stages of maturation produce different
levels of IL-12 p70 heterodimer and induce different patterns of Th1-
and Th2-type cytokine production in Th cells, DC harvested at different
time points after the initiation of their maturation were cocultured
with freshly isolated CD4+ Th cells in the presence of
superantigen (SEB).
|
compared with immature DC (Fig. 2A). This increased IFN-
induction by more mature DC was paralleled by a similar increase in the
induction of the Th2-type cytokine, IL-5. IL-4 was undetectable in
these cultures of SEB-stimulated CD4+ Th cells.
|
is a cofactor in the induction of IL-12 p70 by
CD40L-expressing Th cells 9, 13 , the increasing levels of IFN-
induced in Th cells by more mature DC did not correlate with the
changes in IL-12 p70 production. The induction of final DC maturation
resulted in a transiently elevated ability to produce IL-12 at early
time points (2 and 4 h) of maturation, followed by the decline of
this ability, that was evident in DC matured for 12 h and to an
even greater extent in fully mature DC at 48 h (Fig. 2
A). As an average of four different donors, during
cocultures with Th cells mature DC produced only 19% (range, 7–32%)
of the IL-12 produced by immature DC despite the fact that mature DC
displayed higher levels of CD40 expression (Fig. 1) and induced higher
IFN- production in Th cells.
The diminished IL-12 levels in the cultures containing mature DC could
result from the decreased ability of mature DC to produce this cytokine
or, alternatively, could result from its consumption by more strongly
stimulated Th cells or from their production of some putative
inhibitory factors. To distinguish among these possibilities, DC at
different stages of maturation were stimulated with a soluble CD40L
trimer (sCD40L) plus IFN-, a mode of stimulation that mimics the
physiological IL-12-induction by CD4+ T cells 9, 13 . As
shown in Fig. 2B, the maturation-dependent changes in the
ability to produce IL-12 were observed after this mode of DC
stimulation, indicating that the decreased ability to produce IL-12 is
indeed an intrinsic property of mature DC. Interestingly, after
stimulation with CD40L plus IFN-, the eventual down-regulation of
IL-12 production in fully mature DC was preceded by an initial
transient up-regulation of this ability at 4 h after the induction
of final maturation of DC.
Mature DC show a decreased production of IL-12, but not of IL-6, in
response to CD40 ligation and IFN-
To test whether the reduced ability of mature DC to produce IL-12
is not due to impaired CD40 signaling or to a general decrease in their
metabolic activity, we compared the production of IL-12 and another DC
cytokine IL-6 11, 29, 30 after the stimulation of mature and immature
DC with a combination of sCD40L plus IFN- or with CD40L-transfected
J558 cells (J558-CD40L). As reported previously, stimulation of
immature DC with sCD40L requires the presence of IFN- 9, 10, 13 ,
while J558-CD40L can induce IL-12 p70 in the absence of IFN- 7 ,
which may result from the very high levels of their CD40L expression.
Consistent with the previous set of experiments, CD40-mediated
stimulation of mature DC resulted in reproducibly lower production of
IL-12 p70 (Fig. 3, A and
B). This was especially evident after the stimulation with
CD40L plus IFN-, but, interestingly, it was much less pronounced
after the IFN--independent stimulation with J558-CD40L. These
functional changes appear to be independent from the mode of induction
of final DC maturation, since similar observations were made using
either DC matured in response to IL-1ß and TNF- or DC matured in
response to LPS (Fig. 3B).
|
, C and D),
demonstrating that their CD40-mediated signaling pathway is
undisturbed. Mature DC are resistant to the bacterial cytokine inducers, LPS and SAC
Several previous studies demonstrated the induction of IL-12 p70
production in immature DC by bacterial products, LPS and SAC 9, 10, 11 .
Both these factors are known to induce low level IL-12 p70 production
in the absence of IFN-, and their combination with IFN- results
in high IL-12 p70 production 9, 10, 13 . In contrast to IL-12, the
production of IL-6 is relatively IFN- independent 11, 27, 31 .
In accord with the previous reports 9, 10, 11 , SAC and LPS alone induced
low, but clearly detectable, production of IL-12 p70 in immature DC
(Fig. 3B). Their effectiveness was strongly up-regulated in
the presence of IFN-. The ability to produce IL-12 in response to
SAC or LPS, alone or in combination with IFN-, was abolished in
fully mature DC. Surprisingly, although mature DC were good producers
of IL-6 (Fig. 3, C and D; as well as of IL-8;
data from three donors; not shown) after CD40 triggering, they did not
produce these cytokines after exposure to SAC or LPS, suggesting a
general loss of responsiveness of mature DC to these bacterial stimuli.
Mature DC show reduced responsiveness to IFN- and express
reduced levels of IFN-R
The differential pattern of regulation of the ability of maturing
DC to produce IL-12 p70 and IL-6 suggested a modulation of IFN-
responsiveness in the course of final DC maturation. Therefore, taking
advantage of the ability of CD40L-transfected J558 cells to induce
substantial amounts of IL-12 p70 in either DC type in the absence of
IFN- (Fig. 3, A and B), we tested whether the
production of IL-12, in response to this mode of stimulation, could be
enhanced by IFN- to a similar extent in mature and immature DC.
As shown in Fig. 4A, at the
concentration of 10 U/ml, IFN- strongly up-regulated IL-12 p70
production in immature DC. This IFN- effect was dose dependent up to
1000 U/ml. In contrast, although mature DC did respond to IFN-, the
effect of this cytokine was much less pronounced. In view of the
previously reported requirement for IFN- in the induction of the p35
subunit of IL-12 and the production of biologically active IL-12 p70
heterodimer 13, 27, 32 , these observations suggest that the decreased
production of IL-12 by mature DC interacting with Th results mainly
from their reduced ability to receive IFN--mediated signals. To gain
insight into the mechanism of the decreased responsiveness to IFN-,
we analyzed the expression of surface IFN-R (-chain IFN-R;
CD119) on DC at different stages of maturation. Consistent with their
decreased responsiveness to IFN-, maturing DC displayed
progressively reduced levels of surface expression of CD119 (Fig. 4B).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
R on mature DC and their impaired responsiveness to IFN-. In
contrast to the reduced IL-12 production, the ability of mature DC to
produce IL-6 in response to CD40 triggering is preserved or even
enhanced. This indicates that in contrast to the lost susceptibility of
mature DC to exogenous cytokine inducers, such as bacterial LPS or SAC,
mature DC preserve an intact CD40-mediated signaling pathway involved
in the communication within the immune system. Taking into account the
previous observations that IFN- is an important cofactor in the
CD40-induced high level IL-12 p70 production 9, 13 , the current data
suggest that the selectively reduced ability of maturing DC to produce
bioactive IL-12 results from their reduced responsiveness to IFN-.
The preserved ability of mature DC to produce IL-6, a factor known to
costimulate the proliferation of naive Th cells 33 , may contribute to
their high efficiency as the initiators of primary responses. This
issue is currently being studied. The issue of a changing ability to produce IL-12 in DC at different stages of development and maturation has been addressed previously. A study in a murine model demonstrated that mature DC produce higher levels of IL-12 than their early proliferating precursors 34 . However, in that study an intermediate population of nonproliferating immature DC was not available for comparison. This may explain the different results from the current report, which compares mature DC with nonproliferating immature DC, functionally corresponding to tissue-type DC 15 .
The reduced ability of mature DC to produce IL-12 and their impaired
responsiveness to bacterial stimuli and to IFN- are consistent with
different functions of DC, performed at different stages of their
maturation. At the spot of infection, immature DC are likely to be
activated by the pathogen itself, which requires their responsiveness
to bacterial products. Recently, it was shown that LPS or
Toxoplasma gondii extract induces migration of DC from
nonlymphoid tissues and their in vivo production of the p40 subunit of
IL-12 12 . Such a direct induction of IL-12 by pathogens will be
especially important for the activation of effector mechanisms in the
initial phase of immune response in infected tissues, when only few, if
any, Ag-specific memory/effector T cells are available to induce the
production of IL-12. Since such an early local response is usually
induced by a single pathogen, the fact that pathogen-induced or Th
cell-induced IL-12 is secreted in high amounts and will also reach all
the effector cells in the vicinity does not carry with it the risk of
dysregulating other responses to unrelated Ags. On the contrary, this
may be beneficial, since high levels of IL-12 may be required for the
optimal activation of other than Th types of responding cells, such as
class I-restricted CTLs or NK cells, which can recognize infected or
transformed cells but not necessarily be able to specifically interact
with DC themselves.
This is in sharp contrast to the situation in the lymph nodes. In a recent study Sangster et al. showed that the responses characterized by different Th-dependent isotypes (IgG2a and IgA dominated) to different viruses do not affect each other, even when they are induced simultaneously in the same lymph nodes 35 . An independent regulation of the simultaneously induced responses with different characters against different Ags in a single lymph node requires their functional isolation. This indicates that DC-derived signals should only affect these T cells, which can directly interact with Ag-loaded DC. The risk of affecting other Th cells that have different Ag specificities can be reduced by reducing the amounts of IL-12 released by mature DC.
On the other hand, the resistance of mature DC to IL-12-modulating
factors may help the cells to avoid influences from the responses to
unrelated Ags occurring in the same lymph node. Previously, we have
reported that the levels of IL-12 produced by DC during the
presentation of Ag to Th cells are strongly affected by the previous
experience of mature DC, i.e., by the conditions in which they develop
10 and are induced to mature 36 . While DC matured under the
influence of IL-1ß and TNF- produce intermediate levels of IL-12
and induce the development of Th0/Th1-like cytokine profiles in naive
Th cells, final DC maturation in the additional presence of a common
inflammatory mediator, PGE2 37 , leads to the development
of mature CD1a+CD83+ DC that show a reduced
ability to produce IL-12 and induce Th2-biased differentiation of naive
Th cells 36 . The ability of DC to produce IL-12 is affected to a
similar extent by another inflammatory mediator, IL-10. However, IL-10,
in contrast to PGE2, inhibits the process of final DC
maturation 36 , which may lead to the development of a suppressive DC
type 38, 39 . Despite their strong IL-12 inhibitory activity on
immature and maturing DC, neither PGE2 nor IL-10 can
inhibit IL-12 production in DC that have completed final maturation
36 . Together with the current data, these observations suggest a
general resistance of mature DC to IL-12-modulating factors. These
maturation-associated changes in susceptibility to modulatory factors
may help DC to acquire the signals affecting the initial polarization
of primary immune response (signal 3), to the relevant site of the
infected tissue and to avoid further modification of this message
within the lymph nodes. This aim may be additionally facilitated by the
resistance of mature DC to soluble pathogen-derived IL-12 inducers,
such as LPS, which can reach all the DC within the lymph node
regardless of their source of origin, and the antigenic message they
carry. These maturation-associated changes in the susceptibility of DC
to IL-12-modulating factors resemble the changing ability of DC to take
up Ag, which is up-regulated at the onset of final DC maturation and is
subsequently shut down 23, 28 .
While the interaction of naive Th cells with DC results in only limited
amounts of IL-12 production 6, 9, 13, 40 , the functional significance
of such low doses of IL-12 was demonstrated in the mouse by showing
that neutralization of IL-12 activity in the cultures of TCR transgenic
naive Th cells with spleen-isolated DC results in the reduced IFN-
production 6 . Although we could not quantitate the amounts of IL-12
induced in maturing DC by naive Th cells due to their low levels
(2–10% the amounts induced by bulk CD4+ Th cells) 9, 13 , the current study suggests that the differences in the kinetics of
DC migration may result in different IL-12 levels in the lymph nodes
and may affect the character of the Ag-specific response subsequently
induced.
The observation of strong maturation stage-dependent differences in the IL-12-producing capacity of DC generated in FCS-supplemented cultures raises the question of whether similar maturation-related differences are also present in DC obtained in the presence of autologous serum or in serum-free conditions that are used in immunotherapeutic protocols. The demonstration of similar differences may help in designing optimal strategies for the therapeutic induction of Th1-type responses with the use of DC.
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Pawe Kaliski, Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. E-mail address:
3 Abbreviations used in this paper: DC, dendritic cells; SAC, Staphylococcus aureus Cowan I strain; sCD40L, soluble CD40 ligand trimer; SEB, staphylococcal enterotoxin B; J558-CD40L, CD40 ligand-transfected J558 cells.
Received for publication August 11, 1998. Accepted for publication December 11, 1998.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
. J. Exp. Med. 4:1109.
of lipopolysaccharide-inducible p35 and p40 genes. Blood 2:646.
ß TCR transgenic mice: IL-12 substitution for macrophages to stimulate IFN- production is IFN--dependent. Int. Immunol. 9:1119.
This article has been cited by other articles:
|
|
 |
|
  S. J. A. M. Santegoets, A. J. M. van den Eertwegh, A. A. van de Loosdrecht, R. J. Scheper, and T. D. de Gruijl Human dendritic cell line models for DC differentiation and clinical DC vaccination studies J. Leukoc. Biol., December 1, 2008; 84(6): 1364 - 1373. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-J. Lee, K. A. Foon, R. B. Mailliard, R. Muthuswamy, and P. Kalinski Type 1-polarized dendritic cells loaded with autologous tumor are a potent immunogen against chronic lymphocytic leukemia J. Leukoc. Biol., July 1, 2008; 84(1): 319 - 325. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-E. Lamhamedi-Cherradi, R. E. Martin, T. Ito, F. Kheradmand, D. B. Corry, Y.-J. Liu, and M. Moyle Fungal Proteases Induce Th2 Polarization through Limited Dendritic Cell Maturation and Reduced Production of IL-12 J. Immunol., May 1, 2008; 180(9): 6000 - 6009. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Kim, S. H. Kim, S. Kim, D. Cho, and T. S. Kim AIMP1/p43 Protein Induces the Maturation of Bone Marrow-Derived Dendritic Cells with T Helper Type 1-Polarizing Ability J. Immunol., March 1, 2008; 180(5): 2894 - 2902. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K.-C. Chang, G.-C. Huang, D. Jones, and Y.-H. Lin Distribution Patterns of Dendritic Cells and T Cells in Diffuse Large B-Cell Lymphomas Correlate with Prognoses Clin. Cancer Res., November 15, 2007; 13(22): 6666 - 6672. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Fan, X.-L. Huang, P. Kalinski, S. Young, and C. R. Rinaldo Jr. Dendritic Cell Function during Chronic Hepatitis C Virus and Human Immunodeficiency Virus Type 1 Infection Clin. Vaccine Immunol., September 1, 2007; 14(9): 1127 - 1137. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Perona-Wright, S. M. Anderton, S. E. M. Howie, and D. Gray IL-10 permits transient activation of dendritic cells to tolerize T cells and protect from central nervous system autoimmune disease Int. Immunol., September 1, 2007; 19(9): 1123 - 1134. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Braun, L. Galibert, T. Nakajima, H. Saito, V. V. Quang, M. Rubio, and M. Sarfati Semimature Stage: A Checkpoint in a Dendritic Cell Maturation Program That Allows for Functional Reversion after Signal-Regulatory Protein-{alpha} Ligation and Maturation Signals J. Immunol., December 15, 2006; 177(12): 8550 - 8559. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Laffont, J. D. Coudert, L. Garidou, L. Delpy, A. Wiedemann, C. Demur, C. Coureau, and J.-C. Guery CD8+ T-cell-mediated killing of donor dendritic cells prevents alloreactive T helper type-2 responses in vivo Blood, October 1, 2006; 108(7): 2257 - 2264. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Dauer, K. Schad, J. Junkmann, C. Bauer, J. Herten, R. Kiefl, M. Schnurr, S. Endres, and A. Eigler IFN-{alpha} promotes definitive maturation of dendritic cells generated by short-term culture of monocytes with GM-CSF and IL-4 J. Leukoc. Biol., August 1, 2006; 80(2): 278 - 286. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Tada, S. Aiba, K.-I. Shibata, T. Ohteki, and H. Takada Synergistic Effect of Nod1 and Nod2 Agonists with Toll-Like Receptor Agonists on Human Dendritic Cells To Generate Interleukin-12 and T Helper Type 1 Cells Infect. Immun., December 1, 2005; 73(12): 7967 - 7976. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. T. Rubio, T. K. Means, R. Chakraverty, J. Shaffer, Y. Fudaba, M. Chittenden, A. D. Luster, and M. Sykes Maturation of human monocyte-derived dendritic cells (MoDCs) in the presence of prostaglandin E2 optimizes CD4 and CD8 T cell-mediated responses to protein antigens: role of PGE2 in chemokine and cytokine expression by MoDCs Int. Immunol., December 1, 2005; 17(12): 1561 - 1572. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Hokey, A. T. Larregina, G. Erdos, S. C. Watkins, and L. D. Falo Jr. Tumor Cell Loaded Type-1 Polarized Dendritic Cells Induce Th1-Mediated Tumor Immunity Cancer Res., November 1, 2005; 65(21): 10059 - 10067. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Collins, J. Wolfe, K. Roessner, C. Shi, L. H. Sigal, and R. C. Budd Lyme Arthritis Synovial {gamma}{delta} T Cells Instruct Dendritic Cells via Fas Ligand J. Immunol., November 1, 2005; 175(9): 5656 - 5665. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. P. Moran, M. Collier, K. P. McKinnon, N. L. Davis, R. E. Johnston, and J. S. Serody A Novel Viral System for Generating Antigen-Specific T Cells J. Immunol., September 1, 2005; 175(5): 3431 - 3438. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. B. Mailliard, A. Wankowicz-Kalinska, Q. Cai, A. Wesa, C. M. Hilkens, M. L. Kapsenberg, J. M. Kirkwood, W. J. Storkus, and P. Kalinski {alpha}-Type-1 Polarized Dendritic Cells: A Novel Immunization Tool with Optimized CTL-inducing Activity Cancer Res., September 1, 2004; 64(17): 5934 - 5937. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Mandrekar, D. Catalano, A. Dolganiuc, K. Kodys, and G. Szabo Inhibition of Myeloid Dendritic Cell Accessory Cell Function and Induction of T Cell Anergy by Alcohol Correlates with Decreased IL-12 Production J. Immunol., September 1, 2004; 173(5): 3398 - 3407. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Wassink, P. L. Vieira, H. H. Smits, G. A. Kingsbury, A. J. Coyle, M. L. Kapsenberg, and E. A. Wierenga ICOS Expression by Activated Human Th Cells Is Enhanced by IL-12 and IL-23: Increased ICOS Expression Enhances the Effector Function of Both Th1 and Th2 Cells J. Immunol., August 1, 2004; 173(3): 1779 - 1786. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kubo, H. K. Takahashi, M. Takei, H. Iwagaki, T. Yoshino, N. Tanaka, S. Mori, and M. Nishibori E-Prostanoid (EP)2/EP4 Receptor-Dependent Maturation of Human Monocyte-Derived Dendritic Cells and Induction of Helper T2 Polarization J. Pharmacol. Exp. Ther., June 1, 2004; 309(3): 1213 - 1220. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Movassagh, D. Laderach, and A. Galy Proteins of the Ikaros family control dendritic cell maturation required to induce optimal Th1 T cell differentiation Int. Immunol., June 1, 2004; 16(6): 867 - 875. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Kondo, H. Matsuse, I. Machida, T. Kawano, S. Saeki, S. Tomari, Y. Obase, C. Fukushima, and S. Kohno Regulation of Mite Allergen-pulsed Murine Dendritic Cells by Respiratory Syncytial Virus Am. J. Respir. Crit. Care Med., February 15, 2004; 169(4): 494 - 498. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. P. Oliveira, G. M. A. C. Lima, M. T. Shio, P. J. M. Leenen, and I. A. Abrahamsohn Immature macrophages derived from mouse bone marrow produce large amounts of IL-12p40 after LPS stimulation J. Leukoc. Biol., November 1, 2003; 74(5): 857 - 867. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kuipers, D. Hijdra, V. C. de Vries, H. Hammad, J.-B. Prins, A. J. Coyle, H. C. Hoogsteden, and B. N. Lambrecht Lipopolysaccharide-Induced Suppression of Airway Th2 Responses Does Not Require IL-12 Production by Dendritic Cells J. Immunol., October 1, 2003; 171(7): 3645 - 3654. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Jefford, M. Schnurr, T. Toy, K.-A. Masterman, A. Shin, T. Beecroft, T. Y. Tai, K. Shortman, M. Shackleton, I. D. Davis, et al. Functional comparison of DCs generated in vivo with Flt3 ligand or in vitro from blood monocytes: differential regulation of function by specific classes of physiologic stimuli Blood, September 1, 2003; 102(5): 1753 - 1763. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Laderach, D. Compagno, O. Danos, W. Vainchenker, and A. Galy RNA Interference Shows Critical Requirement for NF-{kappa}B p50 in the Production of IL-12 by Human Dendritic Cells J. Immunol., August 15, 2003; 171(4): 1750 - 1757. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Skelton, M. Cooper, M. Murphy, and A. Platt Human Immature Monocyte-Derived Dendritic Cells Express the G Protein-Coupled Receptor GPR105 (KIAA0001, P2Y14) and Increase Intracellular Calcium in Response to its Agonist, Uridine Diphosphoglucose J. Immunol., August 15, 2003; 171(4): 1941 - 1949. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Camporeale, A. Boni, G. Iezzi, E. Degl'Innocenti, M. Grioni, A. Mondino, and M. Bellone Critical Impact of the Kinetics of Dendritic Cells Activation on the in Vivo Induction of Tumor-specific T Lymphocytes Cancer Res., July 1, 2003; 63(13): 3688 - 3694. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Morrow, B. Slobedman, A. L. Cunningham, and A. Abendroth Varicella-Zoster Virus Productively Infects Mature Dendritic Cells and Alters Their Immune Function J. Virol., April 15, 2003; 77(8): 4950 - 4959. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G-X Zhang, M Kishi, H Xu, and A Rostami Mature bone marrow-derived dendritic cells polarize Th2 response and suppress experimental autoimmune encephalomyelitis Multiple Sclerosis, December 1, 2002; 8(6): 463 - 468. [Abstract] [PDF]
|
|
|
|
|
|
B. Wirleitner, D. Reider, S. Ebner, G. Bock, B. Widner, M. Jaeger, H. Schennach, N. Romani, and D. Fuchs Monocyte-derived dendritic cells release neopterin J. Leukoc. Biol., December 1, 2002; 72(6): 1148 - 1153. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Rosenzwajg, F. Jourquin, L. Tailleux, and J. C. Gluckman CD40 ligation and phagocytosis differently affect the differentiation of monocytes into dendritic cells J. Leukoc. Biol., December 1, 2002; 72(6): 1180 - 1189. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Lindstedt, B. Johansson-Lindbom, and C. A. K. Borrebaeck Global reprogramming of dendritic cells in response to a concerted action of inflammatory mediators Int. Immunol., October 1, 2002; 14(10): 1203 - 1213. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Osugi, S. Vuckovic, and D. N. J. Hart Myeloid blood CD11c+ dendritic cells and monocyte-derived dendritic cells differ in their ability to stimulate T lymphocytes Blood, September 26, 2002; 100(8): 2858 - 2866. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Coudert, C. Coureau, and J.-C. Guery Preventing NK Cell Activation by Donor Dendritic Cells Enhances Allospecific CD4 T Cell Priming and Promotes Th Type 2 Responses to Transplantation Antigens J. Immunol., September 15, 2002; 169(6): 2979 - 2987. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Gauzzi, I. Canini, P. Eid, F. Belardelli, and S. Gessani Loss of Type I IFN Receptors and Impaired IFN Responsiveness During Terminal Maturation of Monocyte-Derived Human Dendritic Cells J. Immunol., September 15, 2002; 169(6): 3038 - 3045. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. E. Lokshin, P. Kalinski, R. R. Sassi, R. B. Mailliard, J. Muller-Berghaus, W. J. Storkus, X. Peng, A. M. Marrangoni, R. P. Edwards, and E. Gorelik Differential regulation of maturation and apoptosis of human monocyte-derived dendritic cells mediated by MHC class II Int. Immunol., September 1, 2002; 14(9): 1027 - 1037. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Luft, M. Jefford, P. Luetjens, T. Toy, H. Hochrein, K.-A. Masterman, C. Maliszewski, K. Shortman, J. Cebon, and E. Maraskovsky Functionally distinct dendritic cell (DC) populations induced by physiologic stimuli: prostaglandin E2 regulates the migratory capacity of specific DC subsets Blood, July 30, 2002; 100(4): 1362 - 1372. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. G.S. van Halteren, E. van Etten, E. C. de Jong, R. Bouillon, B. O. Roep, and C. Mathieu Redirection of Human Autoreactive T-Cells Upon Interaction With Dendritic Cells Modulated by TX527, an Analog of 1,25 Dihydroxyvitamin D3 Diabetes, July 1, 2002; 51(7): 2119 - 2125. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ebner, S. Hofer, V. A. Nguyen, C. Furhapter, M. Herold, P. Fritsch, C. Heufler, and N. Romani A Novel Role for IL-3: Human Monocytes Cultured in the Presence of IL-3 and IL-4 Differentiate into Dendritic Cells That Produce Less IL-12 and Shift Th Cell Responses Toward a Th2 Cytokine Pattern J. Immunol., June 15, 2002; 168(12): 6199 - 6207. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Iyonaga, K. M. McCarthy, and E. E. Schneeberger Dendritic Cells and the Regulation of a Granulomatous Immune Response in the Lung Am. J. Respir. Cell Mol. Biol., June 1, 2002; 26(6): 671 - 679. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Luft, P. Luetjens, H. Hochrein, T. Toy, K.-A. Masterman, M. Rizkalla, C. Maliszewski, K. Shortman, J. Cebon, and E. Maraskovsky IFN-{alpha} enhances CD40 ligand-mediated activation of immature monocyte-derived dendritic cells Int. Immunol., April 1, 2002; 14(4): 367 - 380. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. MacDonald and E. J. Pearce Cutting Edge: Polarized Th Cell Response Induction by Transferred Antigen-Pulsed Dendritic Cells Is Dependent on IL-4 or IL-12 Production by Recipient Cells J. Immunol., April 1, 2002; 168(7): 3127 - 3130. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. B. Mailliard, S. Egawa, Q. Cai, A. Kalinska, S. N. Bykovskaya, M. T. Lotze, M. L. Kapsenberg, W. J. Storkus, and P. Kalinski Complementary Dendritic Cell-activating Function of CD8+ and CD4+ T Cells: Helper Role of CD8+ T Cells in the Development of T Helper Type 1 Responses J. Exp. Med., February 19, 2002; 195(4): 473 - 483. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. C. de Jong, P. L. Vieira, P. Kalinski, J. H. N. Schuitemaker, Y. Tanaka, E. A. Wierenga, M. Yazdanbakhsh, and M. L. Kapsenberg Microbial Compounds Selectively Induce Th1 Cell-Promoting or Th2 Cell-Promoting Dendritic Cells In Vitro with Diverse Th Cell-Polarizing Signals J. Immunol., February 15, 2002; 168(4): 1704 - 1709. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Frasca, C. Scotta, G. Lombardi, and E. Piccolella Human Anergic CD4+ T Cells Can Act as Suppressor Cells by Affecting Autologous Dendritic Cell Conditioning and Survival J. Immunol., February 1, 2002; 168(3): 1060 - 1068. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Buelens, E. J. Bartholome, Z. Amraoui, M. Boutriaux, I. Salmon, K. Thielemans, F. Willems, and M. Goldman Interleukin-3 and interferon beta cooperate to induce differentiation of monocytes into dendritic cells with potent helper T-cell stimulatory properties Blood, February 1, 2002; 99(3): 993 - 998. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Luft, M. Jefford, P. Luetjens, H. Hochrein, K.-A. Masterman, C. Maliszewski, K. Shortman, J. Cebon, and E. Maraskovsky IL-1{beta} Enhances CD40 Ligand-Mediated Cytokine Secretion by Human Dendritic Cells (DC): A Mechanism for T Cell-Independent DC Activation J. Immunol., January 15, 2002; 168(2): 713 - 722. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Sanchez-Torres, G. S. Garcia-Romo, M. A. Cornejo-Cortes, A. Rivas-Carvalho, and G. Sanchez-Schmitz CD16+ and CD16- human blood monocyte subsets differentiate in vitro to dendritic cells with different abilities to stimulate CD4+ T cells Int. Immunol., December 1, 2001; 13(12): 1571 - 1581. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Maldonado-Lopez, C. Maliszewski, J. Urbain, and M. Moser Cytokines Regulate the Capacity of CD8{alpha}+ and CD8{alpha}- Dendritic Cells to Prime Th1/Th2 Cells In Vivo J. Immunol., October 15, 2001; 167(8): 4345 - 4350. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. T. Semnani, H. Sabzevari, R. Iyer, and T. B. Nutman Filarial Antigens Impair the Function of Human Dendritic Cells during Differentiation Infect. Immun., September 1, 2001; 69(9): 5813 - 5822. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Latour, H. Tanaka, C. Demeure, V. Mateo, M. Rubio, E. J. Brown, C. Maliszewski, F. P. Lindberg, A. Oldenborg, A. Ullrich, et al. Bidirectional Negative Regulation of Human T and Dendritic Cells by CD47 and Its Cognate Receptor Signal-Regulator Protein-{alpha}: Down-Regulation of IL-12 Responsiveness and Inhibition of Dendritic Cell Activation J. Immunol., September 1, 2001; 167(5): 2547 - 2554. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. K. Wesa and A. Galy IL-1{beta} induces dendritic cells to produce IL-12 Int. Immunol., August 1, 2001; 13(8): 1053 - 1061. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Abe, S. C. Donnelly, T. Peng, R. Bucala, and C. N. Metz Peripheral Blood Fibrocytes: Differentiation Pathway and Migration to Wound Sites J. Immunol., June 15, 2001; 166(12): 7556 - 7562. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Kalinski, P. L. Vieira, J. H. N. Schuitemaker, E. C. de Jong, and M. L. Kapsenberg Prostaglandin E2 is a selective inducer of interleukin-12 p40 (IL-12p40) production and an inhibitor of bioactive IL-12p70 heterodimer Blood, June 1, 2001; 97(11): 3466 - 3469. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Corinti, C. Albanesi, A. la Sala, S. Pastore, and G. Girolomoni Regulatory Activity of Autocrine IL-10 on Dendritic Cell Functions J. Immunol., April 1, 2001; 166(7): 4312 - 4318. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Grohmann, F. Fallarino, S. Silla, R. Bianchi, M. L. Belladonna, C. Vacca, A. Micheletti, M. C. Fioretti, and P. Puccetti CD40 Ligation Ablates the Tolerogenic Potential of Lymphoid Dendritic Cells J. Immunol., January 1, 2001; 166(1): 277 - 283. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ebner, G. Ratzinger, B. Krosbacher, M. Schmuth, A. Weiss, D. Reider, R. A. Kroczek, M. Herold, C. Heufler, P. Fritsch, et al. Production of IL-12 by Human Monocyte-Derived Dendritic Cells Is Optimal When the Stimulus Is Given at the Onset of Maturation, and Is Further Enhanced by IL-4 J. Immunol., January 1, 2001; 166(1): 633 - 641. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Banchereau, B. Pulendran, R. Steinman, and K. Palucka Will the Making of Plasmacytoid Dendritic Cells in Vitro Help Unravel Their Mysteries? J. Exp. Med., December 18, 2000; 192(12): f39 - f44. [Full Text] [PDF]
|
|
|
|
|
|
S.-i. Hashimoto, T. Suzuki, S. Nagai, T. Yamashita, N. Toyoda, and K. Matsushima Identification of genes specifically expressed in human activated and mature dendritic cells through serial analysis of gene expression Blood, September 15, 2000; 96(6): 2206 - 2214. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Kalinski, H. H. Smits, J. H. N. Schuitemaker, P. L. Vieira, M. van Eijk, E. C. de Jong, E. A. Wierenga, and M. L. Kapsenberg IL-4 Is a Mediator of IL-12p70 Induction by Human Th2 Cells: Reversal of Polarized Th2 Phenotype by Dendritic Cells J. Immunol., August 15, 2000; 165(4): 1877 - 1881. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Vendetti, J.-G. Chai, J. Dyson, E. Simpson, G. Lombardi, and R. Lechler Anergic T Cells Inhibit the Antigen-Presenting Function of Dendritic Cells J. Immunol., August 1, 2000; 165(3): 1175 - 1181. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Tada, A. Asahina, K. Nakamura, M. Tomura, H. Fujiwara, and K. Tamaki Granulocyte/Macrophage Colony-Stimulating Factor Inhibits IL-12 production of Mouse Langerhans Cells J. Immunol., May 15, 2000; 164(10): 5113 - 5119. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. L. Vieira, E. C. de Jong, E. A. Wierenga, M. L. Kapsenberg, and P. Kalinski Development of Th1-Inducing Capacity in Myeloid Dendritic Cells Requires Environmental Instruction J. Immunol., May 1, 2000; 164(9): 4507 - 4512. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Aicher, M. Hayden-Ledbetter, W. A. Brady, A. Pezzutto, G. Richter, D. Magaletti, S. Buckwalter, J. A. Ledbetter, and E. A. Clark Characterization of Human Inducible Costimulator Ligand Expression and Function J. Immunol., May 1, 2000; 164(9): 4689 - 4696. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Braun, E. Lahey, and B. L. Kelsall Selective Suppression of IL-12 Production by Chemoattractants J. Immunol., March 15, 2000; 164(6): 3009 - 3017. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Penna and L. Adorini 1{alpha},25-Dihydroxyvitamin D3 Inhibits Differentiation, Maturation, Activation, and Survival of Dendritic Cells Leading to Impaired Alloreactive T Cell Activation J. Immunol., March 1, 2000; 164(5): 2405 - 2411. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
