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*
Baylor Institute for Immunology Research, Dallas, TX 75204;
School of Dental Medicine, State University of New York, Stony Brook, NY 11794; and
Department of Periodontology and Oral Biology, Boston University School of Medicine, Boston, MA 02118
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, but
little or no IL-4, IL-13, and IL-5. In contrast, P.
gingivalis LPS induced Th and T cell responses characterized by
significant levels of IL-13, IL-5, and IL-10, but lower levels of
IFN-. Consistent with these results, E. coli LPS
induced IL-12(p70) in the CD8
+ dendritic cell (DC)
subset, while P. gingivalis LPS did not. Both LPS,
however, activated the two DC subsets to up-regulate costimulatory
molecules and produce IL-6 and TNF-. Interestingly, these LPS
appeared to have differences in their ability to signal through TLR4;
proliferation of splenocytes and cytokine secretion by splenocytes or
DCs from TLR4-deficient C3H/HeJ mice were greatly impaired in response
to E. coli LPS, but not P. gingivalis
LPS. Therefore, LPS from different bacteria activate DC subsets to
produce different cytokines, and induce distinct types of adaptive
immunity in vivo. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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; in contrast, helminths induce the differentiation of
Th2 cells, whose cytokines (principally IL-4, IL-13, IL-5, and IL-10)
induce IgE- and eosinophil-mediated destruction of the pathogens
(2, 3, 4, 5, 6, 7). While cytokines produced early in the response are
crucial in determining the type of immune response, the mechanism by
which a given pathogen induces a particular type of response is
unknown.
Recently, it was demonstrated that distinct subsets of dendritic cells
(DCs)3 differentially
induce Th1 and Th2 responses (8, 9, 10, 11, 12). In mice, splenic
CD8+ DCs (8, 9, 13) induce Th1
responses, while the CD8- myeloid DCs skew
toward Th2 responses (10, 11). Therefore, it is possible
that a given pathogen may induce a given type of immune response, by
selectively activating a particular DC subset. In this study, we
investigated this hypothesis using LPS from two different strains of
bacteria: 1) E. coli LPS, which signals through the
Toll-like receptor 4 (TLR4) complex (14, 15), and induces
Th cells that secrete high levels of IFN- in vivo (16, 17); 2) LPS from the extracellular, Gram-negative bacterium
Porphyromonas gingivalis that is a causative agent of adult
periodontitis, a chronic inflammatory disease of the oral mucosa
(18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28). P. gingivalis LPS appears less
dependent on TLR4 signaling than E. coli LPS
(18, 19, 20, 21, 22, 23, 24, 25). This property is attributed mainly to the unique
lipid A motif of P. gingivalis LPS, which contains unusually
branched and relatively long fatty acids (19, 20, 23, 24, 25). Unlike enteric LPS, P. gingivalis LPS has been
reported to induce the symptoms of endotoxic shock in C3H/HeJ mice
(19, 20, 23, 24), which have a point mutation in the gene
that encodes TLR4, and are thus hyporesponsive to E. coli
LPS (14, 15). Some clinical studies indicate that during
adult periodontitis caused by P. gingivalis infections,
there is a preponderance of Th2 cytokines and plasma cell infiltration
(26, 27, 28, 29). However, the reason for this is unknown. While
it is becoming appreciated that different microbial products signal
through distinct pattern recognition receptors (30, 31, 32, 33, 34, 35, 36, 37, 38, 39),
the consequences of such differential signaling on the type of adaptive
immune response are not known. The present study was prompted by the
possibility that the different LPS molecules may induce distinct
patterns of immunities by targeting specific DC subsets via TLRs that
are uniquely expressed on the DC subsets. Our data suggest that
although the two LPS induce potent clonal expansion of Ag-specific
CD4+ and CD8+ T cells in
mice, they elicit strikingly different cytokine profiles in the T
cells. Furthermore, these two LPS molecules appear to do this by
eliciting different cytokines by the CD8+ and
CD8- DCs.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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OT-2 TCR transgenic mice (strain 426-6), generated by W. Heath (Walter & Eliza Hall Institute, Melbourne, Australia) and F. Carbone (Monash University, Melbourne, Australia), were obtained from J. Kapp (Emory University, Atlanta, GA). OT-1 TCR transgenic mice were purchased from The Jackson Laboratory (Bar Harbor, ME). C57BL/6 mice, B6.PL.Thy-1a (B6.PL) mice, and C3H/HeJ mice were purchased from The Jackson Laboratory. C3H/HeN mice were purchased from Harlan Sprague Dawley (Indianapolis, IN). All mice were kept in microisolator cages in a specific-pathogen free facility. For adoptive transfers, age-matched, male C57BL/6 or B6.PL.Thy-1a recipients were given 2.5–5 x 106 of either OT-2 cells or OT-1 TCR transgenic T cells i.v.
LPS purification
P. gingivalis strain A7436 and E. coli strain 25922 were cultured under identical conditions and LPS purified, as previously described (40). LPS extraction was achieved by the hot-phenol-water method (41), followed by further purification using isopycnic density gradient centrifugation. Briefly, 10 g (wet weight) bacterial cell pellet was suspended in 35 ml pyrogen-free water, and then 35 ml 90% phenol at 65°C was added dropwise for 20 min and stirred constantly. The aqueous phase was separated by centrifugation at 7000 x g for 20 min and collected. This process was repeated, and the aqueous phase was pooled and dialyzed against deionized water for 3 days. The dialyzed LPS preparation was then subjected to cesium chloride isopycnic density gradient centrifugation (in 0.5837 g CsCl2 4.4 ml of the LPS preparation) at 42,000 rpm for 72 h in a Beckman (Palo Alto, CA) L-60 Ultracentrifuge. The refractive indices of the gradient fractions were determined with a refractometer (Milton Roy, Rochester, NY), and values were converted to density (grams per milliliter). Fractions containing LPS (density fractions between 1.42 and 1.52 g/ml) were pooled, dialyzed against distilled water for 3 days, lyophilized, and stored at room temperature. LPS was analyzed for protein by the Pierce (Rockford, IL) bicinchoninic acid protein assay. LPS samples were also separated by SDS-PAGE and stained for protein with Coomassie blue. Selected samples were also subjected to proteinase K digestion and nuclease treatment and reanalyzed by SDS-PAGE to confirm the purity of the LPS moieties (data not shown).
Endotoxin-free OVA
Chicken OVA (Sigma, St. Louis, MO) was freshly prepared in PBS and depleted of the endotoxin activity (measured by LAL QCL-1000 kit from BioWhittaker, Walkersville, MD), using the Detoxi-Gel Affinity Pack Columns (Pierce). After depletion, the endotoxin level was below the limit of detection of the LAL QCL-1000 kit (<0.1 EU).
Injections
Reconstituted mice (three to five per group) were injected either i.p. or in the footpad, with either 2 mg OVA in saline (Baylor Hospital, Dallas, TX), or 2 mg OVA + 25 µg E. coli LPS, or 2 mg OVA + 25 µg P. gingivalis LPS. Endotoxin activity in saline was measured by LAL QCL-1000 kit, and observed to be below the detection limit. Before mixing with OVA, LPS was sonicated extensively, to ensure uniform mixing of micelles. Footpad injections were given in a volume of 25 µl. i.p. injections were given in a volume of 100 µl.
Flow cytometry
For analyses of OT-2 cells, cell suspensions were prepared from
the draining popliteal lymph nodes or spleens, and incubated on ice
with PE-labeled anti-Thy-1.2 (BD PharMingen, San Diego, CA),
FITC-labeled V2 (BD PharMingen), CyChrome-labeled CD4 (BD
PharMingen), and biotin-labeled V
5 (BD PharMingen), followed by
streptavidin allophycocyanin (ALPC; BD PharMingen). In some of
the experiments, we simply used Thy-1.2 vs CD4. For analyses of OT-1
cells, cell suspensions of draining popliteal lymph nodes or spleens
were stained with PE-labeled anti-Thy-1.2 (BD PharMingen),
FITC-labeled V2 (BD PharMingen), and biotin-labeled CD8 (BD
PharMingen), followed by streptavidin ALPC (BD PharMingen). In some of
the experiments, we simply used V2 vs CD8. DCs were stained with
FITC-labeled CD11c (BD PharMingen), in combination with PE-labeled
CD11b (BD PharMingen), or biotin-labeled CD8 (BD PharMingen),
followed by streptavidin ALPC (BD PharMingen).
In vitro cultures
Four days after priming with OVA or OVA + LPS, 2.5–5 x
105 popliteal lymph node cells (footpad
injections) or splenocytes (i.p. injections) were plated in triplicate
in 96-well round-bottom plates (Costar, Cambridge, MA) in 200 µl RPMI
complete medium supplemented with 5% FBS, together with different
concentrations of OVA, or OVA peptide (SIINFEKL). Proliferative
responses were assessed after 72 h of culture in a humidified
atmosphere of 5% CO2 in air. Cultures were
pulsed with 1 µCi [3H]thymidine for 12
h, and incorporation of the radionucleotide was measured by
-scintillation spectroscopy. For cytokine assays, aliquots of
culture supernatants were removed after 72 h, pooled, and assayed
for the presence of IFN-, IL-2, IL-4, IL-5, and IL-10 by ELISA.
Cytokine ELISAs
IFN-, IL-2, IL-10, IL-4, IL-5, IL-6, IL-12(p70), and TNF-
were quantified by ELISA kits from BD PharMingen, and IL-13 was
measured by an ELISA kit from R&D Systems (Minneapolis, MN).
Purification of DCs
CD11c+CD8+ and
CD11c+CD8- DC subsets
were purified from spleens, as follows. Spleens of C57BL/6 mice were
dissected, cut into small fragments, and then digested with collegenase
D (0.5 mg/ml; Boehringer Mannheim, Mannheim, Germany) and DNase I (40
mg/ml; Boehringer Mannheim) in RPMI 1640 medium supplemented with 5%
FCS for 10 min at 37°C. Digested fragments were washed twice in
PBS/5% FCS. Then, the CD11c+ DCs were enriched
using the CD11c+ microbeads from Miltenyi Biotech
(San Diego, CA). This enrichment process was repeated twice, and the
resulting purity of CD11c+ cells after two rounds
was >90%. The enriched DCs were stained with FITC-conjugated CD11c
(BD PharMingen) and PE-conjugated CD8+ (BD
PharMingen) and sorted into the
CD11c+CD8+ and
CD11c+CD8- subsets,
using a FACSVantage flow cytometer (BD Biosciences, San Jose, CA),
equipped with Enterprise II laser (Coherent Radiatin, Palo Alto, CA).
In some experiments, CD11c+ DCs were enriched
from the spleens of C3H/HeN and C3H/HeJ mice using the
CD11c+ microbeads; the purity of such enriched
DCs was 
90%.
Induction of cytokines from DC subsets
DCs were cultured in RPMIc + 5% FBS with GM-CSF (20 ng/ml) +
IFN- (20 ng/ml), in the presence of either E. coli LPS or
P. gingivalis LPS for 24 or 48 h, and the cytokines
were secreted in the supernatants assayed by ELISA.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We examined whether LPS from E. coli and P.
gingivalis could enhance Ag-specific Th responses against a
soluble protein, such as OVA. To investigate this, we used
OVA-specific, MHC class II-restricted (I-Ab),
TCR transgenic mice (OT-2 mice) (42). In these
mice, the CD4+ OVA-specific T cells express V2
and V5. TCR transgenic T cells were adoptively transferred into
Thy-1 congenic B6.PL.Thy-1a (B6.PL) mice, such
that they constituted a small, but detectable proportion of all T cells
(43). In this system, the fate of OVA-specific, transgenic
T cells was followed using the Thy-1.2 Ab, which stains the transferred
cells, but not the host cells. Cells with the phenotype
Thy-1.2+ CD4+
V2+ V5+ are
considered OVA-specific CD4+ T cells. In some of
the experiments, we simply used Thy-1.2 in combination with CD4, to
detect the OVA-specific T cells.
The reconstituted mice were injected with 2 mg soluble OVA alone, or
OVA + E. coli LPS, or OVA + P. gingivalis LPS,
either i.p. or in the footpads (Fig. 1
).
Before the experiment, OVA was depleted of endotoxin contamination,
using the Detoxi Columns, and tested for endotoxin using the QCL-1000
kit. The CD4+ OVA-specific T cell response either
in the draining lymph nodes or in the spleen was monitored by flow
cytometry (Fig. 2A). Injection
of OVA elicited a significant clonal expansion of the
Thy-1.2+ CD4+ T cells in
the draining lymph nodes of mice, which received footpad injections
(Fig. 2, A, B, and D). Similar
expansions were observed with the i.p. route of injection (Fig. 2, C and E). Both E. coli LPS and
P. gingivalis LPS could significantly enhance the percentage
and absolute numbers of Thy-1.2+
CD4+ T cells, regardless of the route of
injection (Fig. 2). However, P. gingivalis LPS was
marginally better than E. coli LPS in enhancing the clonal
expansion (7% OVA + E. coli LPS vs 9.4% OVA + P.
gingivalis LPS; Fig. 2). Thus, both types of LPS, injected with
OVA, enhanced the clonal expansion of OVA-specific T cells. No
detectable clonal expansion was observed, when either type of LPS was
injected alone (data not shown).
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, F and G, mice that
received an injection of OVA + E. coli LPS, or OVA +
P. gingivalis LPS, had greatly enhanced responses compared
with those that received OVA alone (Fig. 2, F and
G). Either type of LPS alone did not result in any
significant proliferation (data not shown). E. coli LPS and P. gingivalis LPS induce distinct types of Ag-specific Th responses in vivo
Cytokine production by Ag-specific T cells was measured by
assaying the culture supernatants from the cultures described above for
IL-2, IFN-, IL-4, IL-10, and IL-5. Assessment of cytokine production
in these cultures revealed significant differences between mice
injected with OVA, OVA + E. coli LPS, and OVA + P.
gingivalis LPS (Fig. 3). In cultures
from mice injected with OVA alone, there was little, if any, IL-2,
IFN-, IL-10, IL-4, or IL-5 produced. In contrast, in cultures from
mice injected with OVA + E. coli LPS, there was significant
IL-2, IL-10, and very high levels of IFN- produced by the
Ag-specific T cells. Neither IL-4 nor IL-5 could be detected. However,
in cultures from mice injected with OVA + P. gingivalis LPS,
there was a striking diminution of IFN- production, despite
significant production of IL-2 and the Th2 cytokines IL-10 and IL-5
(Fig. 3). In fact, the level of IFN- was as low as that observed
with OVA alone. Therefore, while both types of LPS elicit potent clonal
expansion of Ag-specific CD4+ T cells in vivo,
E. coli LPS + OVA induces a Th1-like response, characterized
by high levels of IFN-. In contrast, P. gingivalis LPS +
OVA induces a response that is essentially devoid of IFN-, and
characterized by significant levels of IL-10 and IL-5, regardless of
the route of injection (Fig. 3). Either type of LPS alone did not
result in any cytokine production in these cultures (data not shown).
No significant levels of IL-4 could be detected in any of the
conditions, and this may reflect the Th1 bias of the C57BL/6 strain
studied. Failure to detect IL-4 was not a peculiarity of the transgenic
system because similar cytokine profiles were observed in experiments
using nontransgenic mice (data not shown).
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). Interestingly, although there is a
titration of IL-13 production with the dose of OVA, even when no OVA
was used there is some basal level of IL-13 production. Whether this is
due to IL-13 production from other cell types (e.g., NK T cells) is
presently under investigation. Therefore, in this system, P.
gingivalis LPS, while shifting the balance toward the Th2 pathway,
does not appear to elicit a classic Th2 response that is characterized
by IL-4 production.
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The strikingly different Th responses induced by E.
coli LPS and P. gingivalis LPS suggested that there may
be differences in Ag-specific CD8+ T cell
responses. We investigated this using OT-1 mice
(H-2Kb-restricted, OVA-specific TCR transgenic
mice) (45, 46). A total of 2.5 x
106 or 5 x 106 spleen
cells from OT-1 mice (B6.PL, Thy-1.2) was adoptively transferred into
B6.PL (Thy-1.1) hosts. Cohorts of host mice were injected with either
OVA, OVA + E. coli LPS, or OVA + P.
gingivalis LPS. Clonal expansion of OVA-specific
CD8+ T cells
(CD8+Thy-1.2+) was assessed
by flow cytometry (Fig. 5, A–E). Both E. coli LPS + OVA and P.
gingivalis LPS + OVA enhanced the clonal expansion of OVA-specific
CD8+ T cells, >60-fold (Fig. 5, A–E). LPS alone had no detectable effect (data not
shown).
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, F and G, mice that
received an injection of either E. coli LPS + OVA or
P. gingivalis LPS + OVA had greatly enhanced responses,
compared with those that received OVA alone. Identical results were
obtained when class I-restricted OVA peptide (SIINFEKL) was used to
restimulate the cells in vitro, suggesting that it was indeed the
CD8+ OVA-specific T cells that proliferated in
culture (data not shown). LPS alone did not result in any significant
proliferation (data not shown). E. coli LPS and P. gingivalis LPS induce distinct types of Ag-specific CD8+ T cell responses in vivo
We next examined the cytokines produced in these cultures by
ELISA. As observed with the CD4+ OT-2 cells,
CD8+ OT-1 cells stimulated with OVA alone did not
secrete significant levels of IL-2, IFN-, IL-10, or IL-5 (Fig. 6). Cells from mice injected with
E. coli LPS + OVA produced very high levels of IFN- and
significant IL-10, but no IL-5 (Fig. 6). In contrast, cells from mice
injected with P. gingivalis LPS + OVA produced strikingly
lower levels of IFN-, and significant levels of IL-10 and IL-5 (Fig. 6), consistent with the cytokine patterns observed with OT-2 cells
(Fig. 3). Identical results were obtained when SIINFEKL peptide was
used to restimulate the cells in vitro (data not shown). LPS alone did
not result in any significant cytokine production (data not shown). No
significant levels of IL-4 were detected, and this may reflect the Th1
bias of the C57BL/6 strain.
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+ and CD8- DC subsets in
vivo
Adjuvants and certain microbial products, such as LPS, are known
to activate DCs, thereby enhancing T cell immunity
(47, 48, 49, 50, 51). In this study, we investigated whether both
types of LPS were capable of activating DC subsets in vivo. C57BL/6
mice were injected with 25 µg E. coli LPS, or P.
gingivalis LPS, either s.c., i.p., or i.v., and sacrificed 6
h later. Spleens and lymph nodes were collected, and the expression of
activation markers (CD80, CD86, and CD40) on DCs was determined.
CD8+ and CD8- DC
subsets are well characterized (8, 9, 10, 11, 12, 13, 47, 50, 51, 52, 53), and
may derive from different lineages or may simply reflect different
developmental stages of the same lineage (8, 9, 13).
CD8+ and CD8- DCs
from the spleens of PBS-treated, control mice express significant
levels of CD80, CD86, and CD40, as reported previously
(50). However, upon injection of either type of LPS, there
was a significant up-regulation of CD80, CD86, and CD40 on both DC
subsets (Fig. 7). Therefore, both types
of LPS appear to activate the CD8+ and
CD8- DC subsets in vivo. Similar results were
obtained with the DC subsets in the lymph nodes (data not shown).
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+ DCs
It has been previously shown that splenic
CD8+ DCs can be induced to secrete IL-12 by
various microbial products (8, 9, 10, 50, 51, 52), and that this
IL-12 is influential in the elicitation of Th1 responses by the
CD8+ DC subset (10). In this
study, we wished to determine whether both types of LPS could induce
biologically active IL-12(p70) in CD8+ DCs.
Splenic CD11c+CD8+ and
CD11c+CD8- DC subsets
were isolated by flow cytometry, and cultured for 48 h with either
E. coli LPS, P. gingivalis LPS, or alone. Then
the supernatants were assayed for IL-12, IL-6, and TNF- by ELISA.
Both types of LPS induced IL-6 and TNF- in both DC subsets (Fig. 8). However, only E. coli LPS
induced IL-12 in the CD8+ DC subset (Fig. 8).
Therefore, while both types of LPS could activate both DC subsets, only
the E. coli LPS could elicit the Th-1-inducing cytokine
IL-12, this being consistent with the strikingly different Th responses
induced by E. coli LPS and P. gingivalis LPS in
vivo. Whether P. gingivalis LPS induces Th2 responses by
simply failing to elicit IL-12 in DCs, or whether it actually
stimulates the production of a Th2-inducing cytokine is not known. Good
candidates for Th2-inducing cytokines are IL-10 and IL-4. However,
significant levels of IL-10 or IL-4 could not be consistently detected
in these cultures (data not shown).
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While E. coli LPS mediates its effects by signaling
though TLR4 (14, 15), P. gingivalis LPS is
reported signal through a TLR4-independent mechanism
(18, 19, 20, 21, 22, 23, 24, 25). Thus, we examined the effect(s) of either type
of LPS on proliferation of splenocytes from C3H/HeJ mice, which have a
point mutation in the TLR4 gene, and wild-type (C3H/HeN) mice. C3H/HeJ
splenocytes cultured with E. coli LPS were greatly impaired
in their proliferative capacity, compared with the C3H/HeN controls
(Fig. 9A). In contrast,
C3H/HeJ splenocytes cultured with P. gingivalis LPS were
only modestly impaired in their proliferative capacity, compared with
the C3H/HeN controls (Fig. 9B). Consistent with this,
production of IL-6 induced by E. coli LPS was greatly
impaired in C3H/HeJ splenocytes, compared with C3H/HeN splenocytes
(Fig. 10). However, production of IL-6
induced by P. gingivalis LPS was not impaired in C3H/HeJ
mice (Fig. 10). Furthermore, induction of IL-12 and other cytokines, by
E. coli LPS, from enriched CD11c+
splenic DCs was severely impaired in C3H/HeJ mice; in contrast,
cytokine production induced by P. gingivalis LPS was only
moderately affected (Fig. 11).
Therefore, while E. coli LPS signaling is largely dependent
on TLR4, P. gingivalis LPS appears less dependent on this
pathway.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. In contrast, P. gingivalis LPS induces
OVA-specific T cell responses, characterized by significant levels of
the Th2 cytokines IL-13, IL-5, and IL-10, but lower levels of IFN-.
Consistent with these findings, E. coli LPS induces IL-12
production from CD8+ DCs, while P.
gingivalis LPS does not. These observations are consistent with
several previous reports implicating a central role for IL-12 in
IFN- induction by E. coli LPS (54, 55).
Despite their strikingly different effects on IL-12 production, both
LPS molecules do activate the CD8+ and
CD8- DC subsets, as judged by the production
of IL-6 and TNF-, and the up-regulation of costimulatory
molecules.
Our data also suggest that P. gingivalis LPS is less
dependent on TLR4 signaling than E. coli LPS. This is
consistent with several previous reports, and is attributed mainly to
the unique lipid A motif of P. gingivalis LPS, which
contains unusually branched and relatively long fatty acids, compared
with lipid A from enteric bacterial LPS (19, 20, 23, 24).
Unlike enteric LPS, P. gingivalis LPS has been reported to
induce endotoxic shock in C3H/HeJ mice (19, 20, 23, 24).
These data are consistent with recent findings from Vogel’s group
(25), which suggest that P. gingivalis LPS
activates murine peritoneal macrophages through a TLR4-independent
mechanism to elicit the production of IL-6 and TNF-, but not
IL-12(p70); in contrast, E. coli LPS does induce IL-12(p70)
in macrophages, in addition to IL-6 and TNF- (25).
There could be several mechanisms by which E. coli LPS and
P. gingivalis LPS interact with DCs to elicit distinct
adaptive immune responses, but in principle two opposite kinds of
mechanisms can be envisaged. First, a single DC subset may interpret
distinct microbial or environmental signals differently to yield
distinct types of adaptive immune responses (56, 57, 58). This
instructive model is based on recent reports, which suggest that
apparently homogenous DC subsets can differentially transduce signals
from distinct microbial products or cytokines, to elicit distinct Th
cytokines in vitro (59, 60, 61, 62). In this model, a given DC
subset can elicit virtually any Th response, depending on the
environmental stimulus. In the second selective model, functionally
distinct DC subsets may express distinct repertoires of pattern
recognition receptors that recognize different classes of microbial
products (62). Thus, recognition of a particular microbial
product by a given DC subset will result in a given Th response,
different from that induced by another microbe that activated a
different DC subset. At present, we have limited evidence to
discriminate between these scenarios, with respect to the differential
effects of E. coli and P. gingivalis LPS.
Clearly, both types of LPS activate the CD8+
and CD8- DC subsets (Fig. 8), suggesting that
the signaling receptors for the two types of LPS are present on both
subsets. E. coli LPS activates both DC subsets, most likely
through TLR4, and P. gingivalis LPS activates both DC
subsets, perhaps through a different TLR, expressed on both DC subsets.
In this context, our additional data suggest that mRNA for TLR4 is
expressed on both the CD8+ and the
CD8- DC subsets, as measured by PCR (data not
shown). Further studies are however needed to ascertain surface
expression of the various TLRs on the different DC subsets. Whatever
receptors through which they signal, our data suggest that two distinct
LPS can elicit strikingly different patterns of adaptive immunity, most
likely by stimulating different cytokines in DC subsets. These
observations highlight a central role for distinct DC subsets for
differentially interpreting signals from different microbial products
and instructing the adaptive immune response to mount distinct patterns
of immunity. Although the present study compares the effect of a single
molecule (LPS) from different microbes, it is tempting to speculate
that this may represent a model for how different microorganisms
stimulate distinct types of immunities. Thus, the overall type of
response against the whole microorganism may well be an integration of
all microbial signals through all receptors and all APC subsets.
Whether live pathogens or their extracts do indeed obey the rules
observed for individual microbial products remains to be established.
Finally, these data also point to the use of P. gingivalis
LPS, or its derivatives such as lipid A or synthetic analogues in the
elicitation of therapeutic Th2-like responses in clinical settings.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Bali Pulendran at the current address: Aventis Pharmaceuticals, Route 202-206, P.O. Box 6800, Bridgewater, NJ 08807-0800. E-mail address: BaliPulendran{at}aventis.com
3 Abbreviations used in this paper: DC, dendritic cell; ALPC, allophycocyanin; TLR, Toll-like receptor.
Received for publication July 17, 2001. Accepted for publication August 24, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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/-producing cells link innate and adaptive immunity. J. Exp. Med. 192:219.This article has been cited by other articles:
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  N. C. Peters, D. R. Kroeger, S. Mickelwright, and P. A. Bretscher CD4 T cell cooperation is required for the in vivo activation of CD4 T cells Int. Immunol., November 1, 2009; 21(11): 1213 - 1224. [Abstract] [Full Text] [PDF]
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 S. Nares, N. M. Moutsopoulos, N. Angelov, Z. G. Rangel, P. J. Munson, N. Sinha, and S. M. Wahl Rapid Myeloid Cell Transcriptional and Proteomic Responses to Periodontopathogenic Porphyromonas gingivalis Am. J. Pathol., April 1, 2009; 174(4): 1400 - 1414. [Abstract] [Full Text] [PDF]
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 S.L. Gaffen and G. Hajishengallis A New Inflammatory Cytokine on the Block: Re-thinking Periodontal Disease and the Th1/Th2 Paradigm in the Context of Th17 Cells and IL-17 Journal of Dental Research, September 1, 2008; 87(9): 817 - 828. [Abstract] [Full Text] [PDF]
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 E. Jasny, M. Eisenblatter, K. Matz-Rensing, K. Tenner-Racz, M. Tenbusch, A. Schrod, C. Stahl-Hennig, V. Moos, T. Schneider, P. Racz, et al. IL-12-Impaired and IL-12-Secreting Dendritic Cells Produce IL-23 upon CD154 Restimulation J. Immunol., May 15, 2008; 180(10): 6629 - 6639. [Abstract] [Full Text] [PDF]
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 G. Bachrach, H. Altman, P. E. Kolenbrander, N. I. Chalmers, M. Gabai-Gutner, A. Mor, M. Friedman, and D. Steinberg Resistance of Porphyromonas gingivalis ATCC 33277 to Direct Killing by Antimicrobial Peptides Is Protease Independent Antimicrob. Agents Chemother., February 1, 2008; 52(2): 638 - 642. [Abstract] [Full Text] [PDF]
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 F. W. van Ginkel, T. Iwamoto, B. D. Schultz, and J. M. Tomich Immunity to a Self-Derived, Channel-Forming Peptide in the Respiratory Tract Clin. Vaccine Immunol., February 1, 2008; 15(2): 260 - 266. [Abstract] [Full Text] [PDF]
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 A. Maroof and P. M. Kaye Temporal Regulation of Interleukin-12p70 (IL-12p70) and IL-12-Related Cytokines in Splenic Dendritic Cell Subsets during Leishmania donovani Infection Infect. Immun., January 1, 2008; 76(1): 239 - 249. [Abstract] [Full Text] [PDF]
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N. J. Singh, M. Cox, and R. H. Schwartz TLR Ligands Differentially Modulate T Cell Responses to Acute and Chronic Antigen Presentation J. Immunol., December 15, 2007; 179(12): 7999 - 8008. [Abstract] [Full Text] [PDF]
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 K. Takahashi, S. Satoi, H. Yanagimoto, N. Terakawa, H. Toyokawa, T. Yamamoto, Y. Matsui, S. Takai, A-H. Kwon, and Y. Kamiyama Circulating Dendritic Cells and Development of Septic Complications After Pancreatectomy for Pancreatic Cancer Arch Surg, December 1, 2007; 142(12): 1151 - 1157. [Abstract] [Full Text] [PDF]
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G. Xu, D. Liu, I. Okwor, Y. Wang, H. Korner, S. K. P. Kung, Y.-X. Fu, and J. E. Uzonna LIGHT Is Critical for IL-12 Production by Dendritic Cells, Optimal CD4+ Th1 Cell Response, and Resistance to Leishmania major J. Immunol., November 15, 2007; 179(10): 6901 - 6909. [Abstract] [Full Text] [PDF]
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 D. Skokos and M. C. Nussenzweig CD8- DCs induce IL-12-independent Th1 differentiation through Delta 4 Notch-like ligand in response to bacterial LPS J. Exp. Med., July 9, 2007; 204(7): 1525 - 1531. [Abstract] [Full Text] [PDF]
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S. Hamm, A. Heit, M. Koffler, K. M. Huster, S. Akira, D. H. Busch, H. Wagner, and S. Bauer Immunostimulatory RNA is a potent inducer of antigen-specific cytotoxic and humoral immune response in vivo Int. Immunol., March 1, 2007; 19(3): 297 - 304. [Abstract] [Full Text] [PDF]
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J. Sun and E. J. Pearce Suppression of Early IL-4 Production Underlies the Failure of CD4 T Cells Activated by TLR-Stimulated Dendritic Cells to Differentiate into Th2 Cells J. Immunol., February 1, 2007; 178(3): 1635 - 1644. [Abstract] [Full Text] [PDF]
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L. Chen, M. Arora, M. Yarlagadda, T. B. Oriss, N. Krishnamoorthy, A. Ray, and P. Ray Distinct Responses of Lung and Spleen Dendritic Cells to the TLR9 Agonist CpG Oligodeoxynucleotide J. Immunol., August 15, 2006; 177(4): 2373 - 2383. [Abstract] [Full Text] [PDF]
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C.W. Cutler and R. Jotwani Dendritic Cells at the Oral Mucosal Interface Journal of Dental Research, August 1, 2006; 85(8): 678 - 689. [Abstract] [Full Text] [PDF]
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M. E. Wikstrom, E. Batanero, M. Smith, J. A. Thomas, C. von Garnier, P. G. Holt, and P. A. Stumbles Influence of Mucosal Adjuvants on Antigen Passage and CD4+ T Cell Activation during the Primary Response to Airborne Allergen J. Immunol., July 15, 2006; 177(2): 913 - 924. [Abstract] [Full Text] [PDF]
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 P. G. Tipping Toll-Like Receptors: The Interface between Innate and Adaptive Immunity J. Am. Soc. Nephrol., July 1, 2006; 17(7): 1769 - 1771. [Full Text] [PDF]
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X. Han, S. Wang, Y. Fan, J. Yang, L. Jiao, H. Qiu, and X. Yang Chlamydia Infection Induces ICOS Ligand-Expressing and IL-10-Producing Dendritic Cells That Can Inhibit Airway Inflammation and Mucus Overproduction Elicited by Allergen Challenge in BALB/c Mice J. Immunol., May 1, 2006; 176(9): 5232 - 5239. [Abstract] [Full Text] [PDF]
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 S. Chanchevalap, M. O. Nandan, B. B. McConnell, L. Charrier, D. Merlin, J. P. Katz, and V. W. Yang Kruppel-like factor 5 is an important mediator for lipopolysaccharide-induced proinflammatory response in intestinal epithelial cells Nucleic Acids Res., February 25, 2006; 34(4): 1216 - 1223. [Abstract] [Full Text] [PDF]
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T. Querec, S. Bennouna, S. Alkan, Y. Laouar, K. Gorden, R. Flavell, S. Akira, R. Ahmed, and B. Pulendran Yellow fever vaccine YF-17D activates multiple dendritic cell subsets via TLR2, 7, 8, and 9 to stimulate polyvalent immunity J. Exp. Med., February 21, 2006; 203(2): 413 - 424. [Abstract] [Full Text] [PDF]
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Q. Zhou and S. Amar Identification of Proteins Differentially Expressed in Human Monocytes Exposed to Porphyromonas gingivalis and Its Purified Components by High-Throughput Immunoblotting Infect. Immun., February 1, 2006; 74(2): 1204 - 1214. [Abstract] [Full Text] [PDF]
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F.C. Gibson III, H. Yumoto, Y. Takahashi, H.-H. Chou, and C.A. Genco Innate Immune Signaling and Porphyromonas gingivalis-accelerated Atherosclerosis Journal of Dental Research, February 1, 2006; 85(2): 106 - 121. [Abstract] [Full Text] [PDF]
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N. Foster, J. Cheetham, J.J. Taylor, and P.M. Preshaw VIP Inhibits Porphyromonas gingivalis LPS-induced Immune Responses in Human Monocytes Journal of Dental Research, November 1, 2005; 84(11): 999 - 1004. [Abstract] [Full Text] [PDF]
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M. G. Netea, J. W. M. Van der Meer, R. P. Sutmuller, G. J. Adema, and B.-J. Kullberg From the Th1/Th2 Paradigm towards a Toll-Like Receptor/T-Helper Bias Antimicrob. Agents Chemother., October 1, 2005; 49(10): 3991 - 3996. [Full Text] [PDF]
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 L. Freeman, M. Hewison, S. V. Hughes, K. N. Evans, D. Hardie, T. K. Means, and R. Chakraverty Expression of 11{beta}-hydroxysteroid dehydrogenase type 1 permits regulation of glucocorticoid bioavailability by human dendritic cells Blood, September 15, 2005; 106(6): 2042 - 2049. [Abstract] [Full Text] [PDF]
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M. Sundquist and M. J. Wick TNF-{alpha}-Dependent and -Independent Maturation of Dendritic Cells and Recruited CD11cintCD11b+ Cells during Oral Salmonella Infection J. Immunol., September 1, 2005; 175(5): 3287 - 3298. [Abstract] [Full Text] [PDF]
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D.R. Dixon and R.P. Darveau Lipopolysaccharide Heterogeneity: Innate Host Responses to Bacterial Modification of Lipid A Structure Journal of Dental Research, July 1, 2005; 84(7): 584 - 595. [Abstract] [Full Text] [PDF]
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A. R. Weatherill, J. Y. Lee, L. Zhao, D. G. Lemay, H. S. Youn, and D. H. Hwang Saturated and Polyunsaturated Fatty Acids Reciprocally Modulate Dendritic Cell Functions Mediated through TLR4 J. Immunol., May 1, 2005; 174(9): 5390 - 5397. [Abstract] [Full Text] [PDF]
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E. Marcenaro, M. D. Chiesa, F. Bellora, S. Parolini, R. Millo, L. Moretta, and A. Moretta IL-12 or IL-4 Prime Human NK Cells to Mediate Functionally Divergent Interactions with Dendritic Cells or Tumors J. Immunol., April 1, 2005; 174(7): 3992 - 3998. [Abstract] [Full Text] [PDF]
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B. Pulendran Variegation of the Immune Response with Dendritic Cells and Pathogen Recognition Receptors J. Immunol., March 1, 2005; 174(5): 2457 - 2465. [Abstract] [Full Text] [PDF]
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A. De Creus, M. Abe, A. H. Lau, H. Hackstein, G. Raimondi, and A. W. Thomson Low TLR4 Expression by Liver Dendritic Cells Correlates with Reduced Capacity to Activate Allogeneic T Cells in Response to Endotoxin J. Immunol., February 15, 2005; 174(4): 2037 - 2045. [Abstract] [Full Text] [PDF]
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M. Muthukuru, R. Jotwani, and C. W. Cutler Oral Mucosal Endotoxin Tolerance Induction in Chronic Periodontitis Infect. Immun., February 1, 2005; 73(2): 687 - 694. [Abstract] [Full Text] [PDF]
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J. Sun, M. Walsh, A. V. Villarino, L. Cervi, C. A. Hunter, Y. Choi, and E. J. Pearce TLR Ligands Can Activate Dendritic Cells to Provide a MyD88-Dependent Negative Signal for Th2 Cell Development J. Immunol., January 15, 2005; 174(2): 742 - 751. [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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F. Re and J. L. Strominger IL-10 Released by Concomitant TLR2 Stimulation Blocks the Induction of a Subset of Th1 Cytokines That Are Specifically Induced by TLR4 or TLR3 in Human Dendritic Cells J. Immunol., December 15, 2004; 173(12): 7548 - 7555. [Abstract] [Full Text] [PDF]
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S. E. Erfurth, S. Grobner, U. Kramer, D. S. J. Gunst, I. Soldanova, M. Schaller, I. B. Autenrieth, and S. Borgmann Yersinia enterocolitica Induces Apoptosis and Inhibits Surface Molecule Expression and Cytokine Production in Murine Dendritic Cells Infect. Immun., December 1, 2004; 72(12): 7045 - 7054. [Abstract] [Full Text] [PDF]
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G. J. D. van Mierlo, Z. F. H. M. Boonman, H. M. H. Dumortier, A. Th. den Boer, M. F. Fransen, J. Nouta, E. I. H. van der Voort, R. Offringa, R. E. M. Toes, and C. J. M. Melief Activation of Dendritic Cells That Cross-Present Tumor-Derived Antigen Licenses CD8+ CTL to Cause Tumor Eradication J. Immunol., December 1, 2004; 173(11): 6753 - 6759. [Abstract] [Full Text] [PDF]
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 A L Hart, K Lammers, P Brigidi, B Vitali, F Rizzello, P Gionchetti, M Campieri, M A Kamm, S C Knight, and A J Stagg Modulation of human dendritic cell phenotype and function by probiotic bacteria Gut, November 1, 2004; 53(11): 1602 - 1609. [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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T. Kikuchi, C. L. Hahn, S. Tanaka, S. E. Barbour, H. A. Schenkein, and J. G. Tew Dendritic Cells Stimulated with Actinobacillus actinomycetemcomitans Elicit Rapid Gamma Interferon Responses by Natural Killer Cells Infect. Immun., September 1, 2004; 72(9): 5089 - 5096. [Abstract] [Full Text] [PDF]
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K. A. Eaton, S. M. Logan, P. E. Baker, R. A. Peterson, M. A. Monteiro, and E. Altman Helicobacter pylori with a Truncated Lipopolysaccharide O Chain Fails To Induce Gastritis in SCID Mice Injected with Splenocytes from Wild-Type C57BL/6J Mice Infect. Immun., July 1, 2004; 72(7): 3925 - 3931. [Abstract] [Full Text] [PDF]
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A. Didierlaurent, I. Ferrero, L. A. Otten, B. Dubois, M. Reinhardt, H. Carlsen, R. Blomhoff, S. Akira, J.-P. Kraehenbuhl, and J.-C. Sirard Flagellin Promotes Myeloid Differentiation Factor 88-Dependent Development of Th2-Type Response J. Immunol., June 1, 2004; 172(11): 6922 - 6930. [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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 S. Basu and M. J. Fenton Toll-like receptors: function and roles in lung disease Am J Physiol Lung Cell Mol Physiol, May 1, 2004; 286(5): L887 - L892. [Abstract] [Full Text] [PDF]
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S. Dillon, A. Agrawal, T. Van Dyke, G. Landreth, L. McCauley, A. Koh, C. Maliszewski, S. Akira, and B. Pulendran A Toll-Like Receptor 2 Ligand Stimulates Th2 Responses In Vivo, via Induction of Extracellular Signal-Regulated Kinase Mitogen-Activated Protein Kinase and c-Fos in Dendritic Cells J. Immunol., April 15, 2004; 172(8): 4733 - 4743. [Abstract] [Full Text] [PDF]
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R. Jotwani and C. W. Cutler Fimbriated Porphyromonas gingivalis Is More Efficient than Fimbria-Deficient P. gingivalis in Entering Human Dendritic Cells In Vitro and Induces an Inflammatory Th1 Effector Response Infect. Immun., March 1, 2004; 72(3): 1725 - 1732. [Abstract] [Full Text] [PDF]
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V. Redecke, H. Hacker, S. K. Datta, A. Fermin, P. M. Pitha, D. H. Broide, and E. Raz Cutting Edge: Activation of Toll-Like Receptor 2 Induces a Th2 Immune Response and Promotes Experimental Asthma J. Immunol., March 1, 2004; 172(5): 2739 - 2743. [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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E. Latz, J. Franko, D. T. Golenbock, and J. R. Schreiber Haemophilus influenzae Type b-Outer Membrane Protein Complex Glycoconjugate Vaccine Induces Cytokine Production by Engaging Human Toll-Like Receptor 2 (TLR2) and Requires the Presence of TLR2 for Optimal Immunogenicity J. Immunol., February 15, 2004; 172(4): 2431 - 2438. [Abstract] [Full Text] [PDF]
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C. Johansson and M. J. Wick Liver Dendritic Cells Present Bacterial Antigens and Produce Cytokines upon Salmonella Encounter J. Immunol., February 15, 2004; 172(4): 2496 - 2503. [Abstract] [Full Text] [PDF]
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P. Zhang, M. Martin, Q.-B. Yang, S. M. Michalek, and J. Katz Role of B7 Costimulatory Molecules in Immune Responses and T-Helper Cell Differentiation in Response to Recombinant HagB from Porphyromonas gingivalis Infect. Immun., February 1, 2004; 72(2): 637 - 644. [Abstract] [Full Text] [PDF]
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D. A Murray and J. M. A. Wilton Lipopolysaccharide from the Periodontal Pathogen Porphyromonas gingivalis Prevents Apoptosis of HL60-Derived Neutrophils In Vitro Infect. Immun., December 1, 2003; 71(12): 7232 - 7235. [Abstract] [Full Text] [PDF]
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S. Agrawal, A. Agrawal, B. Doughty, A. Gerwitz, J. Blenis, T. Van Dyke, and B. Pulendran Cutting Edge: Different Toll-Like Receptor Agonists Instruct Dendritic Cells to Induce Distinct Th Responses via Differential Modulation of Extracellular Signal-Regulated Kinase-Mitogen-Activated Protein Kinase and c-Fos J. Immunol., November 15, 2003; 171(10): 4984 - 4989. [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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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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R. B. Mailliard, Y.-I. Son, R. Redlinger, P. T. Coates, A. Giermasz, P. A. Morel, W. J. Storkus, and P. Kalinski Dendritic Cells Mediate NK Cell Help for Th1 and CTL Responses: Two-Signal Requirement for the Induction of NK Cell Helper Function J. Immunol., September 1, 2003; 171(5): 2366 - 2373. [Abstract] [Full Text] [PDF]
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M. Martin, R. E. Schifferle, N. Cuesta, S. N. Vogel, J. Katz, and S. M. Michalek Role of the Phosphatidylinositol 3 Kinase-Akt Pathway in the Regulation of IL-10 and IL-12 by Porphyromonas gingivalis Lipopolysaccharide J. Immunol., July 15, 2003; 171(2): 717 - 725. [Abstract] [Full Text] [PDF]
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 Y.-T. A. Teng THE ROLE OF ACQUIRED IMMUNITY AND PERIODONTAL DISEASE PROGRESSION Critical Reviews in Oral Biology & Medicine, July 1, 2003; 14(4): 237 - 252. [Abstract] [Full Text] [PDF]
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M. Lu, M. Zhang, R. L. Kitchens, S. Fosmire, A. Takashima, and R. S. Munford Stimulus-dependent Deacylation of Bacterial Lipopolysaccharide by Dendritic Cells J. Exp. Med., June 16, 2003; 197(12): 1745 - 1754. [Abstract] [Full Text] [PDF]
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H. Qi, T. L. Denning, and L. Soong Differential Induction of Interleukin-10 and Interleukin-12 in Dendritic Cells by Microbial Toll-Like Receptor Activators and Skewing of T-Cell Cytokine Profiles Infect. Immun., June 1, 2003; 71(6): 3337 - 3342. [Abstract] [Full Text] [PDF]
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 V. Toshchakov, B. W. Jones, A. Lentschat, A. Silva, P.-Y. Perera, K. Thomas, M. J. Cody, Shuling Zhang, B. R.G. Williams, J. Major, et al. TLR2 and TLR4 agonists stimulate unique repertoires of host resistance genes in murine macrophages: interferon-{beta}-dependent signaling in TLR4-mediated responses Innate Immunity, June 1, 2003; 9(3): 169 - 175. [Abstract] [PDF]
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B. N. Gantner, R. M. Simmons, S. J. Canavera, S. Akira, and D. M. Underhill Collaborative Induction of Inflammatory Responses by Dectin-1 and Toll-like Receptor 2 J. Exp. Med., May 5, 2003; 197(9): 1107 - 1117. [Abstract] [Full Text] [PDF]
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C. M. Smith, G. T. Belz, N. S. Wilson, J. A. Villadangos, K. Shortman, F. R. Carbone, and W. R. Heath Cutting Edge: Conventional CD8{alpha}+ Dendritic Cells Are Preferentially Involved in CTL Priming After Footpad Infection with Herpes Simplex Virus-1 J. Immunol., May 1, 2003; 170(9): 4437 - 4440. [Abstract] [Full Text] [PDF]
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L. A.J. O'Neill, A. Dunne, M. Edjeback, P. Gray, C. Jefferies, and C. Wietek Mal and MyD88: adapter proteins involved in signal transduction by Toll-like receptors Innate Immunity, February 1, 2003; 9(1): 55 - 59. [Abstract] [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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P. A. Sieling, W. Chung, B. T. Duong, P. J. Godowski, and R. L. Modlin Toll-Like Receptor 2 Ligands as Adjuvants for Human Th1 Responses J. Immunol., January 1, 2003; 170(1): 194 - 200. [Abstract] [Full Text] [PDF]
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G. Miller, V. G. Pillarisetty, A. B. Shah, S. Lahrs, Z. Xing, and R. P. DeMatteo Endogenous Granulocyte-Macrophage Colony-Stimulating Factor Overexpression In Vivo Results in the Long-Term Recruitment of a Distinct Dendritic Cell Population with Enhanced Immunostimulatory Function J. Immunol., September 15, 2002; 169(6): 2875 - 2885. [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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T. M. Doherty, A. W. Olsen, L. van Pinxteren, and P. Andersen Oral Vaccination with Subunit Vaccines Protects Animals against Aerosol Infection with Mycobacterium tuberculosis Infect. Immun., June 1, 2002; 70(6): 3111 - 3121. [Abstract] [Full Text] [PDF]
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