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*
The Edward Jenner Institute for Vaccine Research, Compton, Berkshire, United Kingdom;
Department of Immunology, University of Glasgow, Glasgow, United Kingdom; and
Department of Immunology, University of Strathclyde, Glasgow, United Kingdom
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and reduced production of IL-4) by Ag-stimulated
CD4+ T cells from the DO.11.10 transgenic mouse expressing
a TCR specific for an OVA peptide (OVA323–339). In contrast, a
phosphorylcholine-containing glycoprotein, ES-62, secreted by the
filarial nematode, Acanthocheilonema viteae, which
generates a Th2 Ab response in vivo, is found to induce the maturation
of dendritic cells (DC2) with the capacity to induce Th2 responses
(increased IL-4 and decreased IFN-). In addition, we show that the
switch to either Th1 or Th2 responses is not effected by differential
regulation through CD80 or CD86 and that a Th2 response is achieved in
the presence of IL-12. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-4. This reflects the capacity of these cells to
generate either a Th1 or a Th2 response (9) and thus
provides a simple model of immune modulation. To determine whether bm-DC can be matured to bias CD4+ T cells to either a Th1 or Th2 phenotype, we embarked on a screening program in which immature DC were precultured with a variety of pathogen products and then used to stimulate cytokine production in such OVA-specific CD4+ cells. While LPS was used to mature DC (DC1) to promote a Th1 response, a phosphorylcholine-containing glycoprotein, ES-62, secreted by the filarial nematode, Acanthocheilonema viteae, was found to induce the maturation of DC (DC2) with the capacity to induce Th2 responses. This pathogen product was chosen because filarial nematodes are parasites that have a propensity to generate a Th2 response in vivo, and such Th2 responses are considered to be associated with parasite longevity (10). Moreover, we had previously shown that this phosphorylcholine-containing glycoprotein, ES-62, has the capacity to modulate lymphocyte activation in vitro and in vivo (11). Thus, we now provide the first evidence that immature bm-DC can be activated in the presence of pathogen products to generate the signals necessary for either a Th1 or Th2 response. These results suggest that DCs in the innate immune system can act as a cellular differentiation "bridge" between pathogens and the subsequent adaptive response.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BALB/c mice were bred at the Institute for Animal Health
(Compton, Berkshire, U.K.) and the Department of Immunology, University
of Strathclyde (Glasgow, U.K.). A DO.11.10 
ß TCR Tg mouse founder
colony was a kind gift from Dr. Fiona Powrie (Nuffield Department of
Surgery, Oxford, U.K.). All Tg mice were assayed for the transgene
using a biotinylated KJ1-26 mAb (a gift from Dr. Powrie) to stain
splenocytes for flow cytometric analysis. All mice used were 6–12 wk
old. The life cycle of the rodent filarial nematode, A.
viteae, was maintained at the University of Strathclyde as
described previously (12).
Preparation of the phosphorylcholine-containing glycoprotein, ES-62
ES-62 was purified from spent culture medium of adult A. viteae by ultrafiltration as described previously (12).
Cell culture
Routine tissue culture of splenocytes and sorted T cells was conducted in RPMI 1640 Glutamax I (Life Technologies, Paisley, U.K.), supplemented with 10% heat-inactivated FCS (Life Technologies), 50 µM 2-ME (Sigma, Poole, Dorset, U.K.), 100 U/ml penicillin, and 100 µg/ml streptomycin (Life Technologies). Bm-DC isolation medium consisted of MEM with Earle’s salts, 25 mM HEPES, and Glutamax I (Life Technologies) supplemented with 2% FCS, while bm-DC culture medium comprised IMDM with Glutamax I, 25 mM HEPES (Life Technologies) supplemented with 10% FCS, 50 µM 2-ME, and 10 ng/ml GM-CSF (R&D Systems, Abingdon, Oxon, U.K.).
Flow cytometry
FITC-conjugated Abs specific for CD4, CD8, B7.1 (CD80), B7.2 (CD86), CD54, and CD40 were purchased from Harlan SeraLabs (Loughborough, Leicestershire, U.K.) along with the relevant isotype controls. MHC class II expression was measured using a FITC-conjugated anti-I-Ad/I-Ed Ab (PharMingen, Oxford, Oxon, U.K.). Flow cytometry was conducted using a FACScalibur Immunocytometry System (Becton Dickinson, Oxford, Oxon, U.K.).
Monoclonal Abs
Blocking mAb to IL-12 (C17.8), IL-10 (JES5-2A5), CD80 (1G10), and CD86 (PO3) were all purchased from PharMingen. CTLA-4-Ig was obtained from R&D Systems.
Culture of bm-DC and treatment with modulins
Femurs and tibias were dissected from mice as previously
described (13) and bone marrow cells seeded into
75-cm2 flasks containing bm-DC culture medium at
37°C in a humidified incubator. On day 4, the supernatant was
carefully removed from the flasks and the cells replenished with fresh
bm-DC culture medium. On day 6, loosely adherent cells were removed by
gentle pipetting and centrifugation and used as immature bm-DC. Such
bm-DC show a marked degree of heterogeneity for many surface molecules
although they are routinely negative for F4/80 (macrophage), CD19 (B
cell), CD3 (T cell), and Gr-1 (granulocytes) (results not shown). In
some experiments presented, these cultures were used as a source of DC.
In other studies, bm-DC were further purified to >95% purity using
magnetic anti-CD11c beads (Fig. 1
)
following the protocol provided the manufacturer (Miltenyi Biotec,
Surrey, U.K.). Following isolation, bm-DC or, where indicated,
CD11c+ bm-DC were plated at 1 x
106 cells/ml in 24-well plates (Falcon; Becton
Dickinson) and further grown in bm-DC culture medium in the presence or
absence of LPS (Escherichia coli serotype 055:B5, Sigma)
(1–10 µg/ml) or ES-62 (1–2 µg/ml) for a further 24 h at
37°C. The cells were then washed three times with PBS before
coculturing with naive CD4+ DO.11.10 Tg T cells.
Essentially the same results were obtained with bm-DC or CD11C plus
bm-DC.
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Purified naive CD4+ CD62Lhigh T cells from DO.11.10 mice were used as source of responder T cells for bm-DC derived from BALB/c mice. Spleens were removed from DO.11.10 mice and passed through 70-µm cell strainers (Falcon; Becton Dickinson). The splenocytes were then washed in RPMI 1640 and resuspended (108 cells/ml) in magnetic activated cell sorter (MACS) buffer (FACSFlow; Becton Dickinson; 0.5% FCS) and incubated with anti-CD4-MACS beads (Miltenyi Biotec). Following purification, the CD4+ cells were subsequently stained with anti-CD62L-FITC and anti-CD4-PE (PharMingen) to allow purification of the naive cells (CD62LhighCD4+) by FACS sorting. Purified naive (CD62LhighCD4+) Tg T cells (105 cells/well) were then cultured in RPMI 1640 plus 10% FCS with the relevant DC and various concentrations of the OVA peptide (323-ISQAVHAAHAEINEAGR-339; obtained from Genosys Europe, Pampisford, Cambridgeshire, U.K.) for 3 days at 37°C. Cells were then pulsed overnight with [3H]thymidine (1 µCi/well; Amersham, Bucks, U.K.), and incorporation into DNA was analyzed following cell harvesting (Tomtec cell harvester; Wallac, Turku, Finland) by liquid scintillation counting (MicroBeta scintillantion counter; Wallac).
Cytokine assays
CD4+ T cells were isolated as described
above and cultured (2.5 x 105 cells) with
either irradiated (2500 rad; source) bm-DC cultures or
CD11c-purified bm-DC (as indicated) (2.5 x
104 cells) in a total volume of 1 ml in 24-well
tissue culture plates (Nunc, Naperville, IL) with or without OVA
peptide at various concentrations for 3 days at 37°C. The cells were
then stimulated with 50 ng/ml PMA (Sigma) and 500 ng/ml ionomycin
(Sigma) overnight. The cell supernatants were then removed and tested
for expression of IL-2, IL-4, IFN-, IL-10, and IL-12 p70 by ELISA
(R&D Systems).
Measurement of IgG1/IgG2a by ELISA
Flat-bottom 96-well plates were coated with PBS, pH 9, containing 1 µg/ml of ES-62 (100 µl/well) and incubated overnight at 4°C. After washing three times with PBS/Tween (0.05% Tween 20 in PBS, pH 7.4), 150 µl of 4% BSA in PBS was added to each well, and plates were incubated for 1 h at 37°C. The plates were then washed as above, and 100 µl of serum serially diluted 1:3 (starting at 1:100) in PBS/Tween was added to duplicate wells and incubated for 1 h at 37°C. After washing, 100 µl of HRP-conjugated Abs specific for IgG1 or IgG2a, diluted 1:20,000 or 1:10,000, respectively, in PBS containing 25% (v/v) sheep serum, were added to each well. Following a 1-h incubation at 37°C and a subsequent wash, 100 µl of substrate solution was added to each well. This solution was prepared by adding 8 µl of hydrogen peroxide and 250 µl of 6 mg/ml tetramethylbenzidine to 25 ml of 0.1 M sodium acetate solution, pH 5.5. The enzymatic reaction was allowed to proceed for 15 min in darkness at room temperature before being stopped by the addition of 50 µl of 10% (v/v) sulfuric acid. The absorbencies were then read at 450 nm on a Titertek Multiskan. Results were expressed as reciprocal endpoint dilutions.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It has been shown previously that murine bm-DC pulsed with varying
doses of peptide (14) and human
CD14+ DC cultured in the presence of
PGE2 (15) can promote differential
regulation of T cell cytokine profiles. Moreover, it has also been
proposed that pattern recognition receptors expressed on APC can
interact with products of pathogens (modulins) to subsequently modify T
cell function. To test this idea, we generated DC from mouse bone
marrow, exposed these cultures to products of pathogens, and then
assessed their ability to modify T cell function in a peptide-specific
Tg system. Culture of GM-CSF-matured bm-DC with either LPS (DC-LPS) or
ES-62 (DC-ES-62) revealed a DC phenotype that promoted increased
proliferation (as indicated by DNA synthesis (Fig. 2a)) of naive
CD4+CD62Lhigh (99% pure,
data not shown) Ag-specific Tg T cells at all concentrations of OVA
peptide tested (1–300 pM), compared with that observed with DC matured
with GM-CSF alone (DC-GM-CSF) (Fig. 2a). Similar enhanced T
cell proliferative responses were obtained using either CD11C plus
bm-DC as stimulators or when alloreactive responder T cells were used
(data not shown). To determine whether the observed increase in
proliferation was associated with either Th1 or Th2 cytokine
production, we cocultured either bm-DC or CD11C+
bm-DC matured under all three conditions together with
OVA-specific T cells and measured the production of the signature Th1
cytokine, IFN-, and the canonical Th2 cytokine, IL-4. The data shown
(Fig. 2b) is derived from experiments using bm-DC although
essentially identical results were obtained using CD11C with or without
DC (results not shown). We found (Fig. 2b), as might have
been predicted from earlier studies showing that LPS-treated APC
promote a Th1 profile of cytokine secretion in
CD4+ T cells that compared with DC-GM-CSF (DC0),
DC-LPS do indeed promote an increase in IFN- (16, 17).
In contrast, DC-ES-62 did not mediate such an increase in IFN- but
rather, at concentrations of OVA peptide >1 nM, appeared to inhibit
IFN- production to below the levels obtained following culture with
DC0 and Tg T cells (Fig. 2b). As it has been widely
established that IL-4 can suppress IFN- production
(18), we speculated that the diminished IFN- production
observed in DC-ES-62/CD4+ T cell cocultures might
be due to the preferential outgrowth of IL-4-producing Th2 cells. As
can be seen from the results presented in Fig. 2c, this is
indeed the case: while DC-LPS suppresses IL-4 production, DC-ES-62
promotes a significant increase in IL-4 levels compared with those
observed in response to DC-GM-CSF. As it has been shown previously that
high Ag doses generally favor a Th1 response (14), we
investigated whether these differential pathogen-mediated effects
on DC maturation simply reflected distinct Ag dose thresholds for these
pathogen products. However, data from five independent experiments
using CD11c+ DC with or without bm-DC clearly showed that
while increasing the concentration of LPS (from 1 to 10 µg/ml) does
indeed further polarize the resulting T cell response toward a Th1-like
phenotype (enhances IFN- (Fig. 2d) and almost completely
suppresses IL-4 production (Fig. 2e), increasing the
concentration of ES-62 (from 1–2 µg/ml) to which the DC are exposed
further biased the response toward a Th2 phenotype (IFN- production
is almost completely suppressed (Fig. 2d) and IL-4
generation is further enhanced (Fig. 2e)).
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DC express on their cell surface a variety of molecules that are
known to be important for both T cell activation and differentiation
(4). However, no single molecule has been identified as
being responsible for driving the differentiation of Th0 cells toward
Th1 or Th2 phenotypes. To further explore the mechanism by which DC can
induce differential T cell cytokine profiles, we used
CD11c+ DC to look for differential expression of candidate
molecules by either DC-LPS (DC1) or DC-ES-62 (DC2) (Fig. 3). These data clearly show that DC-LPS
demonstrate increased expression of CD40, B7.1 (CD80), B7.2 (CD86), and
CD54 relative to DC-GM-CSF. In contrast, DC-ES-62 do not show an
increased expression of any of these markers relative to DC-GM-CSF.
Similar experiments with unpurified bm-DC basically provided identical
results (results not shown). Consistent with our findings above (Fig. 2
, d and e) that increasing the Ag dose does
not necessarily favor development of a Th1 response, we found that MHC
class II expression did not change substantially in either route of DC
differentiation from the, albeit high, levels of MHC class II
expression observed in DC-GM-CSF cells.
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CD80 and CD86 were up-regulated on bm-DC matured in the presence
of LPS but not ES-62 or GM-CSF alone (Fig. 3). Thus, to address whether
CD80/CD86 played a key role in the LPS-mediated development of a Th1
phenotype, we repeated our experiments in the presence of a soluble
CTLA4-Ig fusion protein (Fig. 4,
a and b) to block bidirectional signaling between
CD80/CD86 on the DCs with CD28/CTLA-4 counter-structures on the
OVA-specific DO11.10 Tg T cells. These results showed that while
culture with CTLA4-Ig did indeed block LPS- and ES-62-mediated IFN-
production, it also blocked ES-62/LPS-mediated IL-4 production. Given
that CD80/CD86 have previously been implicated in the development of
polarized Th responses, these results were rather surprising. Thus, to
further directly assess the role of CD80 and/or CD86 in DC-directed
Th1/Th2 differentiation, we also tested the effect of blocking mAbs to
these molecules, either alone or in combination, on the OVA-specific
production of either IFN- or IL-4 (Fig. 4, c and
d). Our data show that while both Th1 and Th2 cytokine
production is only partially blocked with either Ab alone, almost
complete inhibition of both types of cytokine production is seen when
blocking with anti-CD80 and anti-CD86 Abs together (Fig. 4, c and d).
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DC have been reported to produce a number of cytokines that are
known to influence T cell differentiation (19). In
particular, IL-12 and IL-10 have been proposed to reciprocally
influence the induction of IFN- by Th1 cells and Th2 cells
respectively (19). To address the role of these cytokines
in our system, we measured production of either IL-12 or IL-10 by all
three CD11c+ DC phenotypes (Fig. 5, a and b); no
significant production of p70 IL-12 was detected following culture of
DC-GM-CSF, DC-LPS, or DC-ES-62 alone. However, following coincubation
with OVA-specific CD4+ T cells, p70 IL-12
production was dramatically up-regulated in DC-LPS/T cell cultures
(Fig. 5a). Unexpectedly, a smaller but significant increase
in p70 IL-12 production was also observed in DC-ES-62 but not
DC-GM-CSF/T cell cocultures (Fig. 5a).
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b). As there was no
significant difference in the levels of IL-10 produced by cocultures
containing DC-ES-62 or DC-LPS, these results suggested that IL-10 might
not be responsible for the switch from DC0 to DC2 and consequent IL-4
production. However, these results did not preclude the possibility
that any differential IL-10 might be receptor bound or used up at
different rates, events that would influence the levels of available
free IL-10 for detection. Thus to further address the role of these
cytokines in our system, we tested the effects of either recombinant
IL-12, IL-10, or their respective appropriate neutralizing Abs on
cytokine production by our CD11c+ bm-DC/T cell cocultures
(Fig. 6).
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production by all phenotypes of CD11c+
bm-DC/T cell cocultures (Fig. 6a). Similarly, incorporation
of neutralizing anti-IL-12 mAb diminished IFN- production in all
the cultures, thereby confirming the key role of this cytokine in
promoting IFN- production (8, 20). In contrast,
although addition of anti-IL-12 was found, as expected, to
substantially increase IL-4 in these same culture supernatants,
addition of rIL-12 only slightly suppressed IL-4 levels, consistent
with our previous findings that DC-ES-62 promoted a Th2 phenotype
despite the production of substantial levels of p70 IL-12 (Fig. 6b).
The effects of modulating IL-10 levels in these CD11 plus
bm-DC/T cultures was less clear cut; although anti-IL-10
slightly promoted whereas rIL-10 slightly suppressed IFN- production
by DC-LPS/T cell cultures, these reagents had only marginal effects on
cultures containing either DC0 or DC-ES-62 cells (Fig. 6c).
Moreover, whereas addition of rIL-10 appeared to weakly promote an
increase in IL-4 production, anti-IL-10 did not appear to have any
significant effect on the secretion of this cytokine by any of the DC/T
cell cultures (Fig. 6d), a finding that is presumably
consistent with our data (Fig. 5) showing that DC-LPs and DC-ES-62
cultures do not produce significantly different levels of IL-10.
(Fig. 6d).
ES-62 induces a Th2 response in vivo
Our results thus far are consistent with the idea that the innate
immune system, and in particular DC, can be matured by products of
pathogens to acquire the ability to bias an immune response toward
either a Th1 or Th2 phenotype. One consequence of a Th2 response in
vivo is the production of IgG1 in preference to the
Th1-induced Ig isotype, IgG2a (in mice). To assess the
efficacy of ES-62 in induction of an in vivo Th2 response, we therefore
measured IgG1/IgG2a production following s.c. inoculation with ES-62.
The results shown in Fig. 7 clearly
demonstrate a dramatic increase in serum levels of ES-62-specific IgG1.
In contrast, no significant IgG2a response to ES-62 could be
detected.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To address the mechanisms by which such pathogen-matured DC1 and DC2
phenotypes influence Th cell development, we evaluated the role of a
variety of costimulatory molecules and cytokines in the regulation of
Th1 and Th2 cytokine production. First, as it had previously been
proposed that increasing the Ag dose favors development of a Th1
response (14, 21), we investigated whether DC1 and DC2
cells exhibited differential MHC class II expression; however, we found
not only that MHC class II expression did not change significantly in
either route of DC differentiation (Fig. 3) but also that while
increasing the dose of LPS did indeed enhance Th1 development,
increasing the dose of ES-62 promoted further polarization to the Th2
phenotype (Fig. 2). Therefore, these results support our proposal that
the subsequent differentiation of T cells toward a Th1 or Th2 phenotype
in our system is dependent on the nature of the pathogen product rather
than due to an Ag dose effect as has been suggested by others
(14, 22).
Why would the immune system default to a Th1 pathway at high Ag doses?
Previous studies showing induction of a Th1 phenotype in response to
increasing doses of peptide administered in vivo (14)
might simply reflect selective targeting of certain class II-expressing
APC, known to promote development of Th1 cell function
(8), which would not necessarily occur during a normal
immune response following infection with complex pathogen Ags such as
parasites. Alternatively, it has been suggested that signals from
certain costimulatory molecules converge on transduction events
emanating from the TCR, effecting changes in both duration and
amplitude of these signal transduction pathways. Previous findings that
Th1 responses can be induced by high Ag concentration may therefore
simply reflect enhancement of a particular pattern of increased
expression of costimulatory activity and an increase in the relative
avidity of Ag-specific T cell/DC conjugates. In this regard, CD80 and
CD86 have been implicated in the costimulatory process and in IFN-
production, although their exact role with respect to the latter is
controversial (23, 24). Although we found that CD80 and
CD86 were expressed at higher levels in DC-LPS than in DC-ES-62, our
data using CTLA-4-Ig fusion proteins and the appropriate neutralizing
Abs (Fig. 4) suggest that CD80 and CD86 are required for both IL-4 and
IFN- cytokine production, presumably via IL-2 production and T cell
expansion, but are not involved in transmitting DC-derived
differentiation signals. Thus, although our data differs from earlier
reports using CD28- or CD80/86-deficient cells, which suggested that
these interactions play a role in Th2 development (25), it
is consistent with reports proposing that the predominant contribution
of CD80/86 might be to promote proliferation rather than
differentiation (24). In contrast, our finding that DC-LPS
express higher levels of CD54 than DC-ES-62 might be consistent with
recent reports that costimulation via ICAM-1 (CD54) suppresses the
induction of IL-10 and favors the development of Th1 cells
(26). Furthermore, the combination of low expression of
CD54 and CD80 by DC-ES-62 relative to that observed with DC-LPS may
reflect reports that low levels of CD80 expression have been observed
on PBMCs of individuals infected with filarial nematodes (who will have
parasite phosphorylcholine-containing glycoproteins secreted into their
bodies) who demonstrate a poor capacity to make IFN- but an enhanced
capacity to make IL-10 (27). Therefore, a reasonable
explanation for our data is that the interaction of pathogens with DC
induces an increase in a particular pattern of costimulatory molecules
and/or cytokines that subsequently regulate Th0 differentiation and/or
expansion of effector T cells.
All of the candidate costimulatory molecules investigated were shown to
be expressed at lower levels on DC-ES-62 relative to DC-LPS cells (Fig. 3), suggesting that the differentiation and enhanced proliferation of
OVA-specific Th2 cells observed in response to DC-ES reflects
up-regulation of as yet undefined costimulatory molecules during
transition from the DC0 to DC2 phenotype. Alternatively, it was
possible that Th2 induction was due to the production and/or
suppression of cytokines, such as IL-10 or IL-12, which have previously
been implicated in the regulation of differential Th phenotypes, by
DC-ES-62. This possibility seemed particularly pertinent in the light
of previous reports that phosphorylcholine-containing molecules appear
to promote Th2 responses, at least in part, by inducing IL-10
(28). Therefore, we were rather surprised to find not only
that coculture of T cells with DC-ES-62 results in a small but
significant production of IL-12 but also that such cultures do not
produce significantly more IL-10 than those involving DC-LPS (Fig. 5).
However, this can be explained by the target for phosphorylcholine in
the previous studies being shown to be B1 cells (28).
Unlike B1 cells, DCs may not synthesize IL-10 in response to PC or may
synthesize much lower amounts. Our findings were borne out by studies
employing addition of rIL-10 or neutralizing anti-IL-10 Abs, which
suggested that DC-ES-62 may induce Th2 development by a mechanism
independent of IL-10. Moreover, and consistent with the idea that IL-4
is the dominant cytokine when used in combination with IL-12
(18), increased IL-4 production occurs even in the
presence of IL-12 and provides a mechanism for overriding the ability
of this latter cytokine to promote a Th1 response.
In summary, our data clearly support the view that information contained within pathogens is recognized and decoded by DC and that the innate immune system acts as a conduit through which regulation of the adaptive immune response can occur. We propose that DC1 promote a Th1 response and DC2 promote a Th2 response. At present, we are unable to determine whether DC1 and DC2 are derived from a common precursor (DC0) or are expanded from distinct lineages as reported elsewhere (6). However, we have shown that both of these distinct DC phenotypes can be derived from CD11c+ bm-DC precursors. Moreover, although we have shown that the function of CD80/CD86 expression on both DC phenotypes appears to lie in the expansion of differentiated T cells, we have not as yet identified the DC signals responsible for Th subset differentiation. However, these results provide new insights into the nature of Th1/Th2 regulation and suggest potential mechanisms for its manipulation. Vaccination strategies based on the differential activation of DC may be particularly useful in situations where persistence of infection or pathology is associated with specific types of immune response as is the case in filariasis and leishmaniasis (Th2) or respiratory syncytial virus infection and endotoxin-induced shock (Th1). In addition, these data provide the basis for novel future approaches to combating diseases such as allergy, autoimmune disorders, or graft rejection where biasing the Th1/Th2 balance could be of therapeutic benefit.
Finally, it is perhaps ironic but gratifying to see that a molecule that appears to aid a pathogenic organism to persist in its parasitized host can be of value in dissecting the mechanisms underlying immune regulation. However, ES-62 may not be alone in this respect, as recently the protozoan pathogens Plasmodium and Leishmania have been shown to inhibit DC maturation (29, 30). Therefore, DCs may be a common target for infectious agents and hence other "valuable" molecules may await discovery
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Kevin Rigley, The Edward Jenner Institute for Vaccine Research, Compton, Berkshire, RG20 7NN, U.K.
3 Abbreviations used in this paper: DC, dendritic cell; Tg, transgenic; bm-DC, bone marrow-derived DC.
Received for publication August 18, 1999. Accepted for publication March 28, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß-transgenic model. J. Exp. Med. 182:1579.ß TCR transgenic mouse system. Res. Immunol. 144:620.[Medline]
production by Th1 cells in TCR-transgenic models. Immunol. Lett. 65:41.[Medline]
ß-transgenic model. J. Exp. Med. 182:1579.
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 A. S. McKee, M. MacLeod, J. White, F. Crawford, J. W. Kappler, and P. Marrack Gr1+IL-4-producing innate cells are induced in response to Th2 stimuli and suppress Th1-dependent antibody responses Int. Immunol., May 1, 2008; 20(5): 659 - 669. [Abstract] [Full Text] [PDF]
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 A. S. MacDonald and R. M. Maizels Alarming dendritic cells for Th2 induction J. Exp. Med., January 21, 2008; 205(1): 13 - 17. [Abstract] [Full Text] [PDF]
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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]
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R. Rigano, B. Buttari, E. Profumo, E. Ortona, F. Delunardo, P. Margutti, V. Mattei, A. Teggi, M. Sorice, and A. Siracusano Echinococcus granulosus Antigen B Impairs Human Dendritic Cell Differentiation and Polarizes Immature Dendritic Cell Maturation towards a Th2 Cell Response Infect. Immun., April 1, 2007; 75(4): 1667 - 1678. [Abstract] [Full Text] [PDF]
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N. Mejri and M. Brossard Splenic dendritic cells pulsed with Ixodes ricinus tick saliva prime naive CD4+T to induce Th2 cell differentiation in vitro and in vivo Int. Immunol., April 1, 2007; 19(4): 535 - 543. [Abstract] [Full Text] [PDF]
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K. Obayashi, T. Doi, and S. Koyasu Dendritic cells suppress IgE production in B cells Int. Immunol., February 1, 2007; 19(2): 217 - 226. [Abstract] [Full Text] [PDF]
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R. T. Semnani, P. B. Keiser, Y. I. Coulibaly, F. Keita, A. A. Diallo, D. Traore, D. A. Diallo, O. K. Doumbo, S. F. Traore, J. Kubofcik, et al. Filaria-Induced Monocyte Dysfunction and Its Reversal following Treatment. Infect. Immun., August 1, 2006; 74(8): 4409 - 4417. [Abstract] [Full Text] [PDF]
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M. D. Taylor, A. Harris, M. G. Nair, R. M. Maizels, and J. E. Allen F4/80+ Alternatively Activated Macrophages Control CD4+ T Cell Hyporesponsiveness at Sites Peripheral to Filarial Infection. J. Immunol., June 1, 2006; 176(11): 6918 - 6927. [Abstract] [Full Text] [PDF]
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F. A. Marshall, A. M. Grierson, P. Garside, W. Harnett, and M. M. Harnett ES-62, an Immunomodulator Secreted by Filarial Nematodes, Suppresses Clonal Expansion and Modifies Effector Function of Heterologous Antigen-Specific T Cells In Vivo J. Immunol., November 1, 2005; 175(9): 5817 - 5826. [Abstract] [Full Text] [PDF]
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C. E. Loscher, E. Draper, O. Leavy, D. Kelleher, K. H. G. Mills, and H. M. Roche Conjugated Linoleic Acid Suppresses NF-{kappa}B Activation and IL-12 Production in Dendritic Cells through ERK-Mediated IL-10 Induction J. Immunol., October 15, 2005; 175(8): 4990 - 4998. [Abstract] [Full Text] [PDF]
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A. Q. Khan, Q. Chen, Z.-Q. Wu, J. C. Paton, and C. M. Snapper Both Innate Immunity and Type 1 Humoral Immunity to Streptococcus pneumoniae Are Mediated by MyD88 but Differ in Their Relative Levels of Dependence on Toll-Like Receptor 2 Infect. Immun., January 1, 2005; 73(1): 298 - 307. [Abstract] [Full Text] [PDF]
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S. J. Jenkins and A. P. Mountford Dendritic Cells Activated with Products Released by Schistosome Larvae Drive Th2-Type Immune Responses, Which Can Be Inhibited by Manipulation of CD40 Costimulation Infect. Immun., January 1, 2005; 73(1): 395 - 402. [Abstract] [Full Text] [PDF]
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H. S. Goodridge, F. A. Marshall, K. J. Else, K. M. Houston, C. Egan, L. Al-Riyami, F.-Y. Liew, W. Harnett, and M. M. Harnett Immunomodulation via Novel Use of TLR4 by the Filarial Nematode Phosphorylcholine-Containing Secreted Product, ES-62 J. Immunol., January 1, 2005; 174(1): 284 - 293. [Abstract] [Full Text] [PDF]
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H. Kuipers, C. Heirman, D. Hijdra, F. Muskens, M. Willart, S. van Meirvenne, K. Thielemans, H. C. Hoogsteden, and B. N. Lambrecht Dendritic cells retrovirally overexpressing IL-12 induce strong Th1 responses to inhaled antigen in the lung but fail to revert established Th2 sensitization J. Leukoc. Biol., November 1, 2004; 76(5): 1028 - 1038. [Abstract] [Full Text] [PDF]
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D. Jankovic, M. C. Kullberg, P. Caspar, and A. Sher Parasite-Induced Th2 Polarization Is Associated with Down-Regulated Dendritic Cell Responsiveness to Th1 Stimuli and a Transient Delay in T Lymphocyte Cycling J. Immunol., August 15, 2004; 173(4): 2419 - 2427. [Abstract] [Full Text] [PDF]
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X. Zhong, C. Bai, W. Gao, T. B. Strom, and T. L. Rothstein Suppression of expression and function of negative immune regulator PD-1 by certain pattern recognition and cytokine receptor signals associated with immune system danger Int. Immunol., August 1, 2004; 16(8): 1181 - 1188. [Abstract] [Full Text] [PDF]
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H. Matsushima, N. Yamada, H. Matsue, and S. Shimada TLR3-, TLR7-, and TLR9-Mediated Production of Proinflammatory Cytokines and Chemokines from Murine Connective Tissue Type Skin-Derived Mast Cells but Not from Bone Marrow-Derived Mast Cells J. Immunol., July 1, 2004; 173(1): 531 - 541. [Abstract] [Full Text] [PDF]
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H. J. Kim, I. Ifergan, J. P. Antel, R. Seguin, M. Duddy, Y. Lapierre, F. Jalili, and A. Bar-Or Type 2 Monocyte and Microglia Differentiation Mediated by Glatiramer Acetate Therapy in Patients with Multiple Sclerosis J. Immunol., June 1, 2004; 172(11): 7144 - 7153. [Abstract] [Full Text] [PDF]
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R. T. Semnani, M. Law, J. Kubofcik, and T. B. Nutman Filaria-Induced Immune Evasion: Suppression by the Infective Stage of Brugia malayi at the Earliest Host-Parasite Interface J. Immunol., May 15, 2004; 172(10): 6229 - 6238. [Abstract] [Full Text] [PDF]
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J. R. Ramirez-Pineda, A. Frohlich, C. Berberich, and H. Moll Dendritic Cells (DC) Activated by CpG DNA Ex Vivo Are Potent Inducers of Host Resistance to an Intracellular Pathogen That Is Independent of IL-12 Derived from the Immunizing DC J. Immunol., May 15, 2004; 172(10): 6281 - 6289. [Abstract] [Full Text] [PDF]
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A. Mazzoni and D. M. Segal Controlling the Toll road to dendritic cell polarization J. Leukoc. Biol., May 1, 2004; 75(5): 721 - 730. [Abstract] [Full Text] [PDF]
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P. J. Ross, E. C. Lavelle, K. H. G. Mills, and A. P. Boyd Adenylate Cyclase Toxin from Bordetella pertussis Synergizes with Lipopolysaccharide To Promote Innate Interleukin-10 Production and Enhances the Induction of Th2 and Regulatory T Cells Infect. Immun., March 1, 2004; 72(3): 1568 - 1579. [Abstract] [Full Text] [PDF]
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L. Cervi, A. S. MacDonald, C. Kane, F. Dzierszinski, and E. J. Pearce Cutting Edge: Dendritic Cells Copulsed with Microbial and Helminth Antigens Undergo Modified Maturation, Segregate the Antigens to Distinct Intracellular Compartments, and Concurrently Induce Microbe-Specific Th1 and Helminth-Specific Th2 Responses J. Immunol., February 15, 2004; 172(4): 2016 - 2020. [Abstract] [Full Text] [PDF]
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T. Al-Bader, M. Christodoulides, J. E. Heckels, J. Holloway, A. E. Semper, and P. S. Friedmann Activation of Human Dendritic Cells Is Modulated by Components of the Outer Membranes of Neisseria meningitidis Infect. Immun., October 1, 2003; 71(10): 5590 - 5597. [Abstract] [Full Text] [PDF]
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 A J Stagg, A L Hart, S C Knight, and M A Kamm The dendritic cell: its role in intestinal inflammation and relationship with gut bacteria Gut, October 1, 2003; 52(10): 1522 - 1529. [Abstract] [Full Text] [PDF]
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S. Miyazaki, H. Tsuda, M. Sakai, S. Hori, Y. Sasaki, T. Futatani, T. Miyawaki, and S. Saito Predominance of Th2-promoting dendritic cells in early human pregnancy decidua J. Leukoc. Biol., October 1, 2003; 74(4): 514 - 522. [Abstract] [Full Text] [PDF]
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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]
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S. C. Higgins, E. C. Lavelle, C. McCann, B. Keogh, E. McNeela, P. Byrne, B. O'Gorman, A. Jarnicki, P. McGuirk, and K. H. G. Mills Toll-Like Receptor 4-Mediated Innate IL-10 Activates Antigen-Specific Regulatory T Cells and Confers Resistance to Bordetella pertussis by Inhibiting Inflammatory Pathology J. Immunol., September 15, 2003; 171(6): 3119 - 3127. [Abstract] [Full Text] [PDF]
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N. Tsuji, K. Suzuki, H. Kasuga-Aoki, T. Isobe, T. Arakawa, and Y. Matsumoto Mice Intranasally Immunized with a Recombinant 16-Kilodalton Antigen from Roundworm Ascaris Parasites Are Protected against Larval Migration of Ascaris suum Infect. Immun., September 1, 2003; 71(9): 5314 - 5323. [Abstract] [Full Text] [PDF]
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S. Xu, G. K. Koski, M. Faries, I. Bedrosian, R. Mick, M. Maeurer, M. A. Cheever, P. A. Cohen, and B. J. Czerniecki Rapid High Efficiency Sensitization of CD8+ T Cells to Tumor Antigens by Dendritic Cells Leads to Enhanced Functional Avidity and Direct Tumor Recognition Through an IL-12-Dependent Mechanism J. Immunol., September 1, 2003; 171(5): 2251 - 2261. [Abstract] [Full Text] [PDF]
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E. C. Lavelle, E. McNeela, M. E. Armstrong, O. Leavy, S. C. Higgins, and K. H. G. Mills Cholera Toxin Promotes the Induction of Regulatory T Cells Specific for Bystander Antigens by Modulating Dendritic Cell Activation J. Immunol., September 1, 2003; 171(5): 2384 - 2392. [Abstract] [Full Text] [PDF]
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R. T. Semnani, A. Y. Liu, H. Sabzevari, J. Kubofcik, J. Zhou, J. K. Gilden, and T. B. Nutman Brugia malayi Microfilariae Induce Cell Death in Human Dendritic Cells, Inhibit Their Ability to Make IL-12 and IL-10, and Reduce Their Capacity to Activate CD4+ T Cells J. Immunol., August 15, 2003; 171(4): 1950 - 1960. [Abstract] [Full Text] [PDF]
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I. B. McInnes, B. P. Leung, M. Harnett, J. A. Gracie, F. Y. Liew, and W. Harnett A Novel Therapeutic Approach Targeting Articular Inflammation Using the Filarial Nematode-Derived Phosphorylcholine-Containing Glycoprotein ES-62 J. Immunol., August 15, 2003; 171(4): 2127 - 2133. [Abstract] [Full Text] [PDF]
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H. Tezuka, S. Imai, S. Hidano, S. Tsukidate, and K. Fujita Various Types of Dirofilaria immitis Polyproteins Selectively Induce a Th2-Type Immune Response Infect. Immun., July 1, 2003; 71(7): 3802 - 3811. [Abstract] [Full Text] [PDF]
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L. Spencer, L. Shultz, and T. V. Rajan T Cells Are Required for Host Protection against Brugia malayi but Need Not Produce or Respond to Interleukin-4 Infect. Immun., June 1, 2003; 71(6): 3097 - 3106. [Abstract] [Full Text] [PDF]
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S. M. Ellerbroek, K. Wennerberg, and K. Burridge Serine Phosphorylation Negatively Regulates RhoA in Vivo J. Biol. Chem., May 23, 2003; 278(21): 19023 - 19031. [Abstract] [Full Text] [PDF]
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A. M. Woltman and C. van Kooten Functional modulation of dendritic cells to suppress adaptive immune responses J. Leukoc. Biol., April 1, 2003; 73(4): 428 - 441. [Abstract] [Full Text] [PDF]
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A. D. Straw, A. S. MacDonald, E. Y. Denkers, and E. J. Pearce CD154 Plays a Central Role in Regulating Dendritic Cell Activation During Infections That Induce Th1 or Th2 Responses J. Immunol., January 15, 2003; 170(2): 727 - 734. [Abstract] [Full Text] [PDF]
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A. Boonstra, C. Asselin-Paturel, M. Gilliet, C. Crain, G. Trinchieri, Y.-J. Liu, and A. O'Garra Flexibility of Mouse Classical and Plasmacytoid-derived Dendritic Cells in Directing T Helper Type 1 and 2 Cell Development: Dependency on Antigen Dose and Differential Toll-like Receptor Ligation J. Exp. Med., January 6, 2003; 197(1): 101 - 109. [Abstract] [Full Text] [PDF]
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A.-S. Charbonnier, H. Hammad, P. Gosset, G. A. Stewart, S. Alkan, A.-B. Tonnel, and J. Pestel Der p 1-pulsed myeloid and plasmacytoid dendritic cells from house dust mite-sensitized allergic patients dysregulate the T cell response J. Leukoc. Biol., January 1, 2003; 73(1): 91 - 99. [Abstract] [Full Text] [PDF]
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A. A. Bajer, D. Garcia-Tapia, K. R. Jordan, K. M. Haas, D. Werling, C. J. Howard, and D. M. Estes Peripheral blood-derived bovine dendritic cells promote IgG1-restricted B cell responses in vitro J. Leukoc. Biol., January 1, 2003; 73(1): 100 - 106. [Abstract] [Full Text] [PDF]
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Z. Liu, Q. Liu, J. Pesce, J. Whitmire, M. J. Ekkens, A. Foster, J. VanNoy, A. H. Sharpe, J. F. Urban Jr., and W. C. Gause Nippostrongylus brasiliensis Can Induce B7-Independent Antigen-Specific Development of IL-4-Producing T Cells from Naive CD4 T Cells In Vivo J. Immunol., December 15, 2002; 169(12): 6959 - 6968. [Abstract] [Full Text] [PDF]
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B. P. Leung, M. Conacher, D. Hunter, I. B. McInnes, F. Y. Liew, and J. M. Brewer A Novel Dendritic Cell-Induced Model of Erosive Inflammatory Arthritis: Distinct Roles for Dendritic Cells in T Cell Activation and Induction of Local Inflammation J. Immunol., December 15, 2002; 169(12): 7071 - 7077. [Abstract] [Full Text] [PDF]
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R. Stephens and D. D. Chaplin IgE Cross-Linking or Lipopolysaccharide Treatment Induces Recruitment of Th2 Cells to the Lung in the Absence of Specific Antigen J. Immunol., November 15, 2002; 169(10): 5468 - 5476. [Abstract] [Full Text] [PDF]
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A. D. Edwards, S. P. Manickasingham, R. Sporri, S. S. Diebold, O. Schulz, A. Sher, T. Kaisho, S. Akira, and C. Reis e Sousa Microbial Recognition Via Toll-Like Receptor-Dependent and -Independent Pathways Determines the Cytokine Response of Murine Dendritic Cell Subsets to CD40 Triggering J. Immunol., October 1, 2002; 169(7): 3652 - 3660. [Abstract] [Full Text] [PDF]
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D. Werling, R. A. Collins, G. Taylor, and C. J. Howard Cytokine responses of bovine dendritic cells and T cells following exposure to live or inactivated bovine respiratory syncytial virus J. Leukoc. Biol., August 1, 2002; 72(2): 297 - 304. [Abstract] [Full Text] [PDF]
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 P C L Beverley Immunology of vaccination Br. Med. Bull., July 1, 2002; 62(1): 15 - 28. [Abstract] [Full Text] [PDF]
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T. Kaisho, K. Hoshino, T. Iwabe, O. Takeuchi, T. Yasui, and S. Akira Endotoxin can induce MyD88-deficient dendritic cells to support Th2 cell differentiation Int. Immunol., July 1, 2002; 14(7): 695 - 700. [Abstract] [Full Text] [PDF]
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 R. W. Sanders, E. C. de Jong, C. E. Baldwin, J. H. N. Schuitemaker, M. L. Kapsenberg, and B. Berkhout Differential Transmission of Human Immunodeficiency Virus Type 1 by Distinct Subsets of Effector Dendritic Cells J. Virol., June 27, 2002; 76(15): 7812 - 7821. [Abstract] [Full Text] [PDF]
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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]
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H. H. Smits, E. C. de Jong, J. H. N. Schuitemaker, T. B. H. Geijtenbeek, Y. van Kooyk, M. L. Kapsenberg, and E. A. Wierenga Intercellular Adhesion Molecule-1/LFA-1 Ligation Favors Human Th1 Development J. Immunol., February 15, 2002; 168(4): 1710 - 1716. [Abstract] [Full Text] [PDF]
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A. S. MacDonald, M. I. Araujo, and E. J. Pearce Immunology of Parasitic Helminth Infections Infect. Immun., February 1, 2002; 70(2): 427 - 433. [Full Text] [PDF]
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P. McGuirk, C. McCann, and K. H.G. Mills Pathogen-specific T Regulatory 1 Cells Induced in the Respiratory Tract by a Bacterial Molecule that Stimulates Interleukin 10 Production by Dendritic Cells: A Novel Strategy for Evasion of Protective T Helper Type 1 Responses by Bordetella pertussis J. Exp. Med., January 22, 2002; 195(2): 221 - 231. [Abstract] [Full Text] [PDF]
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A. S. MacDonald, A. D. Straw, N. M. Dalton, and E. J. Pearce Cutting Edge: Th2 Response Induction by Dendritic Cells: A Role for CD40 J. Immunol., January 15, 2002; 168(2): 537 - 540. [Abstract] [Full Text] [PDF]
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 M. F. Lipscomb and B. J. Masten Dendritic Cells: Immune Regulators in Health and Disease Physiol Rev, January 1, 2002; 82(1): 97 - 130. [Abstract] [Full Text] [PDF]
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N. Tsuji, K. Suzuki, H. Kasuga-Aoki, Y. Matsumoto, T. Arakawa, K. Ishiwata, and T. Isobe Intranasal Immunization with Recombinant Ascaris suum 14-Kilodalton Antigen Coupled with Cholera Toxin B Subunit Induces Protective Immunity to A. suum Infection in Mice Infect. Immun., December 1, 2001; 69(12): 7285 - 7292. [Abstract] [Full Text] [PDF]
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 M. B. Faries, I. Bedrosian, S. Xu, G. Koski, J. G. Roros, M. A. Moise, H. Q. Nguyen, F. H. C. Engels, P. A. Cohen, and B. J. Czerniecki Calcium signaling inhibits interleukin-12 production and activates CD83+ dendritic cells that induce Th2 cell development Blood, October 15, 2001; 98(8): 2489 - 2497. [Abstract] [Full Text] [PDF]
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 B.N. Lambrecht, J-;B. Prins, and H.C. Hoogsteden Lung dendritic cells and host immunity to infection Eur. Respir. J., October 1, 2001; 18(4): 692 - 704. [Abstract] [Full Text] [PDF]
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G. Caron, Y. Delneste, E. Roelandts, C. Duez, J.-Y. Bonnefoy, J. Pestel, and P. Jeannin Histamine Polarizes Human Dendritic Cells into Th2 Cell-Promoting Effector Dendritic Cells J. Immunol., October 1, 2001; 167(7): 3682 - 3686. [Abstract] [Full Text] [PDF]
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N. Kadowaki, S. Ho, S. Antonenko, R. de Waal Malefyt, R. A. Kastelein, F. Bazan, and Y.-J. Liu Subsets of Human Dendritic Cell Precursors Express Different Toll-like Receptors and Respond to Different Microbial Antigens J. Exp. Med., September 17, 2001; 194(6): 863 - 870. [Abstract] [Full Text] [PDF]
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A. Schonemeyer, R. Lucius, B. Sonnenburg, N. Brattig, R. Sabat, K. Schilling, J. Bradley, and S. Hartmann Modulation of Human T Cell Responses and Macrophage Functions by Onchocystatin, a Secreted Protein of the Filarial Nematode Onchocerca volvulus J. Immunol., September 15, 2001; 167(6): 3207 - 3215. [Abstract] [Full Text] [PDF]
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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]
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A. S. MacDonald, A. D. Straw, B. Bauman, and E. J. Pearce CD8- Dendritic Cell Activation Status Plays an Integral Role in Influencing Th2 Response Development J. Immunol., August 15, 2001; 167(4): 1982 - 1988. [Abstract] [Full Text] [PDF]
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H. S. Goodridge, E. H. Wilson, W. Harnett, C. C. Campbell, M. M. Harnett, and F. Y. Liew Modulation of Macrophage Cytokine Production by ES-62, a Secreted Product of the Filarial Nematode Acanthocheilonema viteae J. Immunol., July 15, 2001; 167(2): 940 - 945. [Abstract] [Full Text] [PDF]
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C. L. King, M. Connelly, M. P. Alpers, M. Bockarie, and J. W. Kazura Transmission Intensity Determines Lymphocyte Responsiveness and Cytokine Bias in Human Lymphatic Filariasis J. Immunol., June 15, 2001; 166(12): 7427 - 7436. [Abstract] [Full Text] [PDF]
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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]
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 A. Lanzavecchia and F. Sallusto Dynamics of T Lymphocyte Responses: Intermediates, Effectors, and Memory Cells Science, October 6, 2000; 290(5489): 92 - 97. [Abstract] [Full Text]
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), 1 µg/ml ES-62 (
), or GM-CSF (
) were washed and then
cocultured with DO.11.10 Tg CD4+ T cells at the indicated
concentrations of OVA peptide before measuring DNA synthesis
(a), IFN-
