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from Human Peripheral Blood Mononuclear Cells in an IL-12- and/or CD28-Dependent Manner
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Lymphokine Regulation Unit, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, and
Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
The Henry M. Jackson Foundation for the Advancement of Military Medicine, U.S. Military HIV Research Program, Bethesda, MD 20889; and
§
Immunex Corp., Seattle, WA 98191
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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are via direct induction of IL-12 and augmentation of
the expression of costimulatory molecules such as B7 from APCs. We
examined the ability of CD40L/CD40 stimulation to regulate the
production of IFN- through IL-12 and/or CD28 costimulation from
human PBMCs stimulated with T cell-specific stimuli. The roles of
exogenous and endogenous CD40L/CD40 stimulation were evaluated using a
trimeric soluble CD40L agonist (CD40T) and an anti-CD40L Ab,
respectively. The presence of CD40T in cultures increased the
production of IL-12 and IFN- from PBMCs stimulated with varying
amounts of PHA. The mechanism, however, by which CD40T enhanced IFN-
varied according to the level of T cell activation. Under maximal
stimulatory conditions (PHA, 1/100), an IL-12-dependent pathway was
dominant. At relatively low levels of T cell stimulation (PHA, 1/500
and 1/1000), however, an additional IL-12-independent CD28-dependent
pathway was elucidated. We further studied the role of exogenous CD28
stimulation in regulating the production of IFN-. The enhancement of
IFN- production induced by direct CD28 stimulation was primarily
dependent on endogenous IL-12 or CD40L/CD40 stimulation. Together,
these data suggest that the production of IFN- involves a complex
interaction between two interdependent, yet distinct, costimulatory
pathways and provide evidence that CD40T may be an effective adjuvant
for the enhancement of responses. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(2, 3). The role that CD40L/CD40
stimulation has in regulating Th1 responses could occur through at
least two mechanisms: the first through direct induction of IL-12 from
APCs such as macrophages and dendritic cells (4, 5, 6, 7), and the second
through the ability of CD40L/CD40 stimulation to enhance the expression
of cell surface molecules such as B7–1, B7–2, intercellular adhesion
molecule-1, and CD44H on APCs, leading to increased T cell stimulation
and production of IFN- (8, 9, 10, 11, 12). The potential importance of
CD40L/CD40 interactions in regulating T cell responses through this
latter pathway was shown in a study in which the induction of B7–2
provided by direct stimulation of CD40 was able to induce an effective
immune response in CD40L-/- mice (13). Moreover, in a
related study, CD40L-/- mice were induced to produce
substantial amounts of IFN- if B7-expressing APCs were adoptively
transferred to these mice (14). Taken together, these results suggest
that in the absence of CD40L/CD40 stimulation, a B7-dependent
costimulatory pathway can mediate a functional Th1 response. It should
be noted, however, that in the aforementioned studies, it was not
determined whether the B-7-directed enhancement of IFN- production
was directly through CD28 and/or required endogenous IL-12
production.
In the experiments described here, the mechanism(s) by which both
endogenous and exogenous CD40L/CD40 stimulation were able to regulate
the production of IL-12 and IFN- from human PBMCs stimulated with T
cell-specific stimuli was studied. A soluble CD40L agonist (CD40T) was
used to examine whether exogenous CD40L/CD40 stimulation could enhance
the production of IFN- at varying levels of T cell activation (15, 16). We subsequently evaluated whether CD40T-mediated enhancement of
IFN- was through an IL-12- and/or a CD28-dependent pathway. Finally,
we showed that direct CD28 stimulation led to an increase in the
production of IFN- that was highly dependent on endogenous IL-12 or
CD40L/CD40 stimulation. Overall, these results provide additional
insight into the interplay between CD40L/CD40 and CD28 costimulatory
pathways in regulating IFN- production. Additionally, these data
support using exogenous CD40L stimulation as a possible vaccine
adjuvant in situations that require a Th1 cellular immune response.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Complete medium consisting of RPMI 1640 supplemented with 10% heat-inactivated human AB sera (Sigma Chemical Co., St. Louis, MO), penicillin (100 U/ml), streptomycin (100 U/ml), and L-glutamine (2 mM) were used for all stimulations. PHA was purchased from Life Technologies (Grand Island, NY). Tetanus toxoid was purchased from Connaught Laboratories (Swiftwater, PA). Lymphocyte separation medium was purchased from Organon Teknika Corp. (Durham, NC).
Subjects
Buffy coat fractions were obtained from apheresed subjects from the National Institutes of Health normal donor pool. All specimens were processed and plated into the appropriate cultures immediately or within 16 h of collection.
Recombinant cytokines
Human rIL-12 with a sp. act. of 5 x 106 U/mg was purchased from R&D Systems, Inc. (Minneapolis, MN). Soluble CD40L (CD40T) was a gift from Immunex Corp. (Seattle, WA).
Antibodies
Goat anti-human IL-12 Ab was purchased from R&D Systems.
Mouse anti-human CD40L (M91) Ab was provided by Immunex Corp. Rat
anti-human IL-10 and mouse anti-human IFN- were purchased
from PharMingen (Torrance, CA). Mouse anti-human CD28 Ab (9.3) and
mouse anti-human anti-CD28 Fab were used as previously
described (17).
Induction of cytokine production by PBMCs
PBMCs were isolated from apheresed buffy coat fractions by
lymphocyte separation medium using the density gradient centrifugation
method. PBMCs (2.5 x 105 cells/250 µl) were
added to round-bottom 96-well plates (Nunc, Copenhagen, Denmark) and
stimulated with PHA and tetanus toxoid in the presence of various
cytokines and/or anticytokines. Supernatants were collected after 4
days of culture for IFN- and stored at -70°C until used.
Supernatants were collected at 40 h to measure the production of
IL-12. Time-course experiments were performed to determine the optimal
time for each cytokine.
Measurement of cytokine production
An IL-12-specific ELISA that detects p70 heterodimer was used
(R&D Systems; lower limit of detection, 7.8 pg/ml). IFN- content was
determined by a two-step ELISA assay (lower limit of detection, 185
pg/ml). There was no background production of IFN- detectable in
medium control wells with or without cytokine adjuvants. Results for
all cytokines represent the mean of triplicate wells. The SEM was
<10% for all experiments.
Flow cytofluorometric analysis
PBMCs were cultured with PHA (1/500 or 1/1000) in the presence or the absence of CD40T or anti-IL-10 (10 µg/ml). At 48 h, cells were dual stained with anti-CD80 PE (Becton Dickinson, Mountain View, CA), CD14 FITC (PharMingen), and isotype control Abs according to the manufacturer’s suggestions. Stained cell populations were analyzed on a FACScan (Becton Dickinson).
Statistical analysis
Normally distributed continuous variable comparisons were performed employing Student’s t test using Microsoft Excel (Redmond, WA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In previous work, it has been shown that CD40L/CD40
stimulation and IL-10 are critical mediators in regulating the
production of IL-12 (5, 18).3 In these initial
experiments, the roles of both CD40L/CD40 stimulation and endogenous
IL-10 in regulating the production of IL-12 from PBMCs in response to T
cell-specific stimuli were studied. In assessing the role of exogenous
CD40L stimulation, a trimeric soluble CD40L agonist (CD40T) was used.
As shown in Figure 1
, addition of CD40T
resulted in a 4-fold increase in IL-12 production
(p < 0.05) from cells stimulated with an
optimal amount of PHA (1/100) compared with that from cells in medium
alone. The addition of CD40T to cultures stimulated with a suboptimal
amount of PHA (1/500) led to a >10-fold increase in IL-12 production
(p < 0.05). The ability of CD40T to enhance
the production of IL-12 was markedly inhibited by addition of
anti-IFN- to the cultures. These data suggest that IFN-, in
addition to its role in priming monocytes for increased IL-12
transcription, is important in enhancing the responsiveness to CD40L
stimulation, possibly by increasing expression of CD40 on APCs (19).
Finally, addition of anti-CD40L Ab to cultures completely inhibited
the induction of IL-12, consistent with previous studies showing that
CD40L/CD40 interaction is critical for induction of IL-12 in response
to T cell-specific stimuli (20).
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CD40L/CD40 stimulation and endogenous IL-10 exert differential
effects on the production of IFN- from PBMCs depending on the degree
of T cell-specific stimulation
In the next series of experiments, the ability of CD40T and
endogenous IL-10 to regulate the production of IFN- in response to
varying doses of PHA and tetanus toxoid was assessed. As shown in
Figure 2, PBMCs stimulated with an
optimal amount of PHA (1/100) in medium alone produced 10 ng/ml of
IFN-, while cells stimulated with a suboptimal amount of PHA
(1/1000) or tetanus toxoid produced substantially less. As a positive
control, addition of IL-12 resulted in a 2- to 3-fold increase in
IFN- production from PBMCs stimulated with PHA (1/100;
p < 0.05) or tetanus toxoid (p
< 0.02) and a 10-fold increase in response to PHA (1/1000;
p < 0.01). Furthermore, addition of CD40T resulted in
a 2-fold increase in IFN- production in cultures stimulated with PHA
(1/100) and tetanus toxoid (p < 0.05) and a
10-fold increase in IFN- production from cells stimulated with PHA
(1/1000; p < 0.02), consistent with the findings shown
in Figure 1
.
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was also studied. Addition of anti-IL-10 to cultures
stimulated with PHA (1/100) resulted in a significant increase in
IFN- (p < 0.01), whereas those cultures
stimulated with PHA (1/1000) or tetanus toxoid had no enhancement.
These data underscore the ability of endogenous IL-10 to limit an
already substantial Th1 response under maximal T cell stimulatory
conditions. Finally, we assessed the role of CD40T in regulating IL-4
production from PBMCs stimulated with the same doses of PHA. In these
experiments, CD40T did not affect the production of IL-4 from PBMCs at
any of the PHA doses tested (data not shown).
Role of endogenous IL-12 and CD28 costimulation in regulating the
production of IFN- from PBMCs stimulated with PHA
The ability of CD40T to enhance IFN- production in response to
PHA could occur by at least two mechanisms. As noted in Figure 1, CD40L/CD40 stimulation leads to enhancement of IL-12 production from
PBMCs stimulated with PHA. A second mechanism could result from a
CD40L/CD40-mediated increase in the expression of B7, which could
subsequently enhance T cell activation, leading to an increase in the
production of IFN-. Thus, we first defined the roles that endogenous
IL-12 and CD28 played in the production of IFN- from PBMCs
stimulated with varying doses of PHA. We then determined whether the
increase in IFN- mediated by the addition of exogenous CD40T was due
to enhancement of IL-12 and/or CD28 costimulation.
As shown in Table I, addition of
anti-IL-12 alone to cultures resulted in a two- to fourfold
reduction of IFN- in response to PHA (1/100). By contrast, there was
no appreciable inhibition of IFN- production from PBMCs stimulated
with PHA (1/500) in the presence of anti-IL-12. These results
suggest that as the amount of PHA used for stimulation is decreased,
there is an IL-12-independent pathway capable of supporting IFN-
production. To assess the role of endogenous CD28 costimulation on the
production of IFN-, anti-CD28 Fab Ab was added to PBMCs
stimulated with PHA. Addition of anti-CD28 Fab resulted in modest
inhibition from cells stimulated with PHA at 1/100 and complete
inhibition of IFN- production from cells stimulated with PHA at
1/500. Similar results were also seen in several experiments using
CTLA-4 Ig to inhibit CD28/B7 costimulation (data not shown). Thus,
these results suggest that when using suboptimal amounts of PHA (1/500
or 1/1000) for stimulation, CD28 costimulation may be a critical
mechanism supporting IL-12-independent production of IFN-.
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through enhancement of
IL-12 and/or CD28 costimulation
Since the production of IFN- could be induced from PBMCs by
different mechanisms depending on the degree of PHA stimulation, the
ability of CD40T to enhance IFN- via IL-12 and/or the CD28
costimulation pathway was evaluated. As shown in Table I, PBMCs
stimulated with suboptimal amounts of PHA (1/500 or 1/1000) in the
presence of CD40T plus anti-IL-12 produced two- to threefold more
IFN- than cells stimulated in the presence of anti-IL-12 alone
and two- to fivefold less IFN- than cells stimulated with CD40T
alone. These data suggest that CD40T at these concentrations of PHA
could enhance IFN- production in both IL-12-dependent and
-independent manners. By contrast, there was no appreciable increase in
the amount of IFN- produced from cells stimulated with PHA (1/100)
in the presence of CD40T plus anti-IL-12 compared with that from
cells given anti-IL-12 alone. Thus, using an optimal amount of PHA
(1/100) for stimulation, the ability of CD40T to enhance IFN- is
predominantly through an IL-12-dependent mechanism, consistent with the
data shown in Figures 1 and 2.
To verify whether the increase in the production of IFN- from PBMCs
stimulated with CD40T was due to CD28 stimulation, anti-CD28 Fab Ab
was added to cultures. As shown in Table I, addition of anti-CD28
Fab in the presence of CD40T markedly inhibited the production of
IFN- from PBMCs stimulated with suboptimal amounts of PHA (1/500 or
1/1000) compared with that from cultures stimulated with CD40T alone.
It should be pointed out that anti-CD28 Fab had a more demonstrable
effect than anti-IL-12 on inhibiting the enhancement of IFN-
induced by CD40T from cells stimulated with PHA (1/500 or 1/1000).
Moreover, additional evidence to support CD28 costimulation having a
role in the ability of CD40T to enhance the production of IFN- under
lower stimulatory conditions was evaluated by assessing the expression
of CD80 on CD14+ cells following stimulation with PHA
(1/500 or 1/1000) in the presence or the absence of CD40T. As shown in
Figure 3, cells cultured with PHA 1/500
or 1/1000 had a three- or sixfold increase in CD80 expression,
respectively. Of interest, the expression of CD86 was not substantially
increased by the presence of CD40T in cultures (data not shown). Thus,
these data support the concept that under lower stimulatory conditions
(1/500 or 1/1000 PHA), addition of CD40T leads to enhanced production
of IFN- via increased B7/CD28 costimulation.
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, addition of anti-IL-10 to cultures stimulated with PHA (1/500 or
1/1000) resulted in a twofold increase in CD80 expression. These data
demonstrate that endogenous IL-10 can influence B7/CD28 costimulation
even at lower levels of T cell activation. It should be noted, however,
that neutralization of endogenous IL-10 did not significantly enhance
the production of IFN- from cells stimulated with PHA (1/1000; Fig. 2). Thus, at lower stimulatory doses of PHA (1/1000), endogenous IL-10
appears to have a less demonstrative role in regulating IFN-, in
contrast to using optimal amounts of PHA (1/100). This further
underscores the role of B7/CD28 costimulation in regulating
CD40T-mediated enhancement of IFN- under low stimulatory
conditions.
Direct CD28 stimulation can induce IFN- production from PBMCs in
response to PHA in the absence of endogenous IL-12 and/or CD40L/CD40
costimulation
In a recent study by Grewal and colleagues (14), it was shown that
IFN- could be induced from CD40L-/- mice by
adoptively transferring APCs expressing B7, suggesting that a
functional IFN- response could be achieved in the absence of
CD40L/CD40 stimulation. In that study, however, it was not determined
whether IFN- induced by the B7-transfected cells was due to a direct
effect on T cells or required an IL-12-dependent positive feedback
loop. Therefore, in the results presented in Table II, we were interested in determining
whether direct CD28 costimulation induced the production of IFN- and
whether this was dependent on endogenous IL-12 and/or CD40L/CD40
stimulation.
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production
was evaluated by adding a stimulatory Ab against CD28 to the cultures.
Under maximal stimulatory conditions (PHA, 1/100), addition of
anti-CD28 alone induced a one- to twofold increase in the
production of IFN-. By contrast, the presence of anti-CD28 Ab
caused a fivefold enhancement of the production of IFN- from cells
stimulated with suboptimal amounts of PHA (1/1000). To determine
whether the enhancement of IFN- induced by anti-CD28 Ab was a
direct effect or was IL-12 dependent, anti-IL-12 was added to
cultures stimulated with anti-CD28 Ab. As shown in Table II, PBMCs
stimulated with PHA at 1/1000 in the presence of anti-CD28 and
anti-IL-12 produced amounts of IFN- similar to those produced
with anti-CD28 alone, suggesting that CD28 stimulation induces a
direct, IL-12-independent enhancement of IFN- at very low
stimulatory conditions. By contrast, in Expt. 1, CD28 stimulation
enhanced IFN- production from cells stimulated with PHA (1/500) both
directly and through an IL-12-dependent pathway.
To assess whether CD28-mediated enhancement of IFN- production was
dependent on CD40L/CD40 stimulation, PBMCs were stimulated with
anti-CD28 Ab in the presence of anti-CD40L Ab. In all the
experiments in which anti-CD28 Ab led to increased production of
IFN-, addition of anti-CD40L Ab resulted in a substantial, but
not complete, reduction in the production of IFN-. Similarly,
addition of anti-IL-12 also abrogated the increase in IFN-
induced by CD28 stimulation, albeit to a lesser extent than
anti-CD40L Ab.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production. With regard to the role of endogenous CD40L/CD40
stimulation in regulating Th1 responses, previous work from both in
vitro (20) and in vivo (2, 3) murine models demonstrated that
CD40L/CD40 stimulation is essential for a functional Th1 response to a
T cell-specific stimulus. In these studies, using human PBMCs
stimulated with PHA, we also show that the induction of IL-12 and
IFN- is highly dependent on CD40L/CD40 stimulation.
Using a soluble CD40L agonist (CD40T), we focused on the ability of
exogenous CD40L/CD40 stimulation to enhance the production of IFN-
from human PBMCs in response to varying levels of T cell activation. In
particular, we studied the roles of IL-12 and/or CD28 costimulation in
mediating the enhancement of IFN- induced by CD40T. Our data show
that when cells are stimulated with an optimal amount of Ag (PHA,
1/100), the CD40T enhancement of IFN- was predominantly through an
IL-12-dependent mechanism. This was consistent with the idea that under
maximal stimulatory conditions a high level of endogenous B7/CD28
costimulation is likely to be already present. When PBMCs were
stimulated with suboptimal amounts of PHA (1/500 or 1/1000), the
presence of CD40T increased IFN- through both IL-12 and B7/CD28
mechanisms. These more limited stimulatory conditions might approximate
what occurs in vivo at the initiation of a primary T cell response in
which the initial interaction of CD40L/CD40 between T cells and APCs
leads to a relatively modest induction of IFN- through a
CD28-dependent, IL-12-independent pathway (23, 24, 25). The availability of
this IFN- may then help enhance subsequent IL-12 induction (26, 27, 28)
as well as IL-12 responsiveness (29). Finally, it is important to note
that endogenous IL-10 production has a major influence on the
regulation of IFN- production. Using optimal amounts of PHA (1/100),
both IL-12 and IL-10 were induced, with the net effect being the
production of IFN- (Fig. 1). Moreover, as shown in Figure 2, the
production of IFN- was further enhanced by addition of
anti-IL-10 at PHA 1/100, but not at PHA 1/1000. In separate
studies, we have noted that the
production of IL-10 from PBMCs occurs in a PHA dose-dependent manner
(data not shown). Thus, the paucity of endogenous IL-10 at low levels
of T cell activation may allow the B7/CD28 costimulation pathway to
support the production of IFN- in the absence of IL-12.
Given these data, which demonstrated a role for CD28 stimulation in
regulating the production of IFN-, we studied the underlying
mechanism by focusing on the role of IL-12 and CD40L/CD40 stimulation.
First, with regard to the role of endogenous CD28 stimulation in
regulating IFN- production, it was shown that addition of
anti-CD28 Fab to cultures stimulated with PHA caused varying
degrees of inhibition of IFN- depending on the amount of PHA used
for stimulation. Furthermore, it was shown that addition of IL-12 to
cultures stimulated in the presence of anti-CD28 Fab led to an
increase in the production of IFN- compared with that by cells
stimulated with anti-CD28 Fab alone; however, it should be noted
that the IFN- produced under these conditions was still
substantially less than that produced in response to IL-12 alone (Table II, Expt. 2). Taken together, these results suggest that endogenous
CD28 stimulation is important in maintaining IL-12 responsiveness,
consistent with a recent report showing that direct CD28 stimulation
increases the expression of IL-12Rß1 chain and IL-12 binding (30) and
would provide a mechanism for the synergy between IL-12 and CD28
stimulation noted in earlier reports (31, 32).
The next series of experiments studied the mechanism by which exogenous
CD28 stimulation could influence IFN- production, again focusing on
the role of IL-12 and CD40L/CD40 stimulation in mediating this effect.
In a previous report, adoptive transfer of B7.1-transfected APCs into
CD40L-/- mice resulted in a functional Th1 response,
providing evidence that CD40L/CD40 stimulation was not essential for
IFN- production provided B7 costimulation was present (14). In our
studies, addition of CD28 Ab to cultures enhanced IFN- in response
to varying amounts of PHA. Moreover, partial enhancement of IFN-
induced by exogenous CD28 stimulation was still maintained even when
anti-CD40L or anti-IL-12 were added to the cultures. These
results are complementary to those obtained by Grewal and co-workers
(14) and provide direct evidence that CD28 stimulation can enhance
IFN- in the absence of CD40L/CD40 stimulation. In addition, they
show that direct CD28 stimulation can enhance IFN- production
independent of IL-12. Finally, it was of interest that in most
experiments the enhancement of IFN- observed by exogenous CD28
stimulation was inhibited more extensively by addition of
anti-CD40L than by addition of anti-IL-12. This observation
could be explained by two mechanisms. The first is that direct CD28
stimulation enhances the expression of CD40L (33), leading to induction
of IL-12, which mediates most of the increase in IFN-. Second, CD40L
up-regulates other costimulatory molecules, e.g., intercellular
adhesion molecule-1 and CD44H along with B7 (10, 34), providing an
additional mechanism to enhance the production of IFN- independent
of IL-12.
Based on the results presented above, our data indicate a hierarchy
among CD40L/CD40 and CD28 costimulatory pathways in regulating the
production of IFN- by PBMCs and suggest that CD40L/CD40 stimulation
may be more important than B7/CD28 stimulation in regulating the
production of IFN- at the population level. This premise is
consistent with in vivo experiments demonstrating that
CD40L-/- mice derived on a resistant background are
highly susceptible to Leishmania major infection
as a result of impaired production of IFN- (35, 36, 37). In contrast,
CD28-/- mice on a resistant background infected with
L. major exhibit relatively normal Th1 responses
and are able to control infection (38). Moreover, DeKruyff et al.
showed that anti-gp39, but not CTLA4-Ig, inhibited IL-12 p40
production from splenic adherent cells stimulated in vitro with Th1
clones plus OVA, providing additional evidence that CD40L/CD40
stimulation has a greater effect on Th1 regulation than does B7/CD28
stimulation (20).
In conclusion, these experiments provide additional insight regarding
the role of CD40L/CD40 stimulation in regulating cellular immune
responses. In addition, this study shows the potent effects that a
soluble CD40L agonist (CD40T) can exert on the production of IL-12 and
IFN- from cells stimulated with T cell-specific Ags. Thus, these
data in conjunction with evidence that CD40L/CD40 stimulation also has
a central role in regulating T cell-dependent Ab production (39, 40)
make CD40T a promising vaccine adjuvant through its ability to enhance
both cellular and humoral immunities.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: CD40L, CD40 ligand; CD40T, trimeric soluble CD40 ligand agonist.
Received for publication July 11, 1997. Accepted for publication October 29, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells. J. Exp. Med. 178:1041. production and type 1 cytokine responses. Immunity 4:471.[Medline]
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D. Burger, N. Molnarfi, L. Gruaz, and J.-M. Dayer Differential Induction of IL-1{beta} and TNF by CD40 Ligand or Cellular Contact with Stimulated T Cells Depends on the Maturation Stage of Human Monocytes J. Immunol., July 15, 2004; 173(2): 1292 - 1297. [Abstract] [Full Text] [PDF]
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Q. Yu, J. X. Gu, C. Kovacs, J. Freedman, E. K. Thomas, and M. A. Ostrowski Cooperation of TNF Family Members CD40 Ligand, Receptor Activator of NF-{kappa}B Ligand, and TNF-{alpha} in the Activation of Dendritic Cells and the Expansion of Viral Specific CD8+ T Cell Memory Responses in HIV-1-Infected and HIV-1-Uninfected Individuals J. Immunol., February 15, 2003; 170(4): 1797 - 1805. [Abstract] [Full Text] [PDF]
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U. Wille, E. N. Villegas, L. Craig, R. Peach, and C. A. Hunter Contribution of Interleukin-12 (IL-12) and the CD28/B7 and CD40/CD40 Ligand Pathways to the Development of a Pathological T-Cell Response in IL-10-Deficient Mice Infect. Immun., December 1, 2002; 70(12): 6940 - 6947. [Abstract] [Full Text] [PDF]
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S. M. L. Montenegro, F. G. C. Abath, A. L. C. Domingues, W. G. Melo, C. N. L. Morais, E. M. Coutinho, S. Mahanty, and T. A. Wynn Enhanced Interleukin-12 and CD40 Ligand Activities but Reduced Staphylococcus aureus Cowan 1-Induced Responses Suggest a Generalized and Progressively Impaired Type 1 Cytokine Pattern for Human Schistosomiasis Infect. Immun., November 1, 2002; 70(11): 5903 - 5912. [Abstract] [Full Text] [PDF]
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M. Wysocka, M. H. Zaki, L. E. French, J. Chehimi, M. Shapiro, S. E. Everetts, K. S. McGinnis, L. Montaner, and A. H. Rook Sezary syndrome patients demonstrate a defect in dendritic cell populations: effects of CD40 ligand and treatment with GM-CSF on dendritic cell numbers and the production of cytokines Blood, October 16, 2002; 100(9): 3287 - 3294. [Abstract] [Full Text] [PDF]
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R. Larkin, C. D. Benjamin, Y.-M. Hsu, Q. Li, L. Zukowski, and R. F. Silver CD40 Ligand (CD154) Does Not Contribute to Lymphocyte-Mediated Inhibition of Virulent Mycobacterium tuberculosis within Human Monocytes Infect. Immun., August 1, 2002; 70(8): 4716 - 4720. [Abstract] [Full Text] [PDF]
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H. J. Cho, T. Hayashi, S. K. Datta, K. Takabayashi, J. H. Van Uden, A. Horner, M. Corr, and E. Raz IFN-{alpha}{beta} Promote Priming of Antigen-Specific CD8+ and CD4+ T Lymphocytes by Immunostimulatory DNA-Based Vaccines J. Immunol., May 15, 2002; 168(10): 4907 - 4913. [Abstract] [Full Text] [PDF]
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K. Pekkari, J. Avila-Carino, A. Bengtsson, R. Gurunath, A. Scheynius, and A. Holmgren Truncated thioredoxin (Trx80) induces production of interleukin-12 and enhances CD14 expression in human monocytes Blood, May 15, 2001; 97(10): 3184 - 3190. [Abstract] [Full Text] [PDF]
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A. Elhofy, I. Marriott, and K. L. Bost Salmonella Infection Does Not Increase Expression and Activity of the High Affinity IL-12 Receptor J. Immunol., September 15, 2000; 165(6): 3324 - 3332. [Abstract] [Full Text] [PDF]
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Y. Cong, C. T. Weaver, A. Lazenby, and C. O. Elson Colitis Induced by Enteric Bacterial Antigen-Specific CD4+ T Cells Requires CD40-CD40 Ligand Interactions for a Sustained Increase in Mucosal IL-12 J. Immunol., August 15, 2000; 165(4): 2173 - 2182. [Abstract] [Full Text] [PDF]
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C. S. Subauste and M. Wessendarp Human Dendritic Cells Discriminate Between Viable and Killed Toxoplasma gondii Tachyzoites: Dendritic Cell Activation After Infection with Viable Parasites Results in CD28 and CD40 Ligand Signaling That Controls IL-12-Dependent and -Independent T Cell Production of IFN-{gamma} J. Immunol., August 1, 2000; 165(3): 1498 - 1505. [Abstract] [Full Text] [PDF]
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M. Dybul, G. Mercier, M. Belson, C. W. Hallahan, S. Liu, C. Perry, B. Herpin, L. Ehler, R. T. Davey, J. A. Metcalf, et al. CD40 Ligand Trimer and IL-12 Enhance Peripheral Blood Mononuclear Cells and CD4+ T Cell Proliferation and Production of IFN-{gamma} in Response to p24 Antigen in HIV-Infected Individuals: Potential Contribution of Anergy to HIV-Specific Unresponsiveness J. Immunol., August 1, 2000; 165(3): 1685 - 1691. [Abstract] [Full Text] [PDF]
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 U. Schonbeck, G. K. Sukhova, K. Shimizu, F. Mach, and P. Libby Inhibition of CD40 signaling limits evolution of established atherosclerosis in mice PNAS, June 20, 2000; 97(13): 7458 - 7463. [Abstract] [Full Text] [PDF]
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I. Gjertsson, O. H. Hultgren, M. Stenson, R. Holmdahl, and A. Tarkowski Are B Lymphocytes of Importance in Severe Staphylococcus aureus Infections? Infect. Immun., May 1, 2000; 68(5): 2431 - 2434. [Abstract] [Full Text] [PDF]
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K. Lukin, M. Cosyns, T. Mitchell, M. Saffry, and A. Hayward Eradication of Cryptosporidium parvum Infection by Mice with Ovalbumin-Specific T Cells Infect. Immun., May 1, 2000; 68(5): 2663 - 2670. [Abstract] [Full Text] [PDF]
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B. Samten, E. K. Thomas, J. Gong, and P. F. Barnes Depressed CD40 Ligand Expression Contributes to Reduced Gamma Interferon Production in Human Tuberculosis Infect. Immun., May 1, 2000; 68(5): 3002 - 3006. [Abstract] [Full Text] [PDF]
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 T. Y. Shibuya, W.-Z. Wei, M. Zormeier, J. Ensley, W. Sakr, R. H. Mathog, R. J. Meleca, G. H. Yoo, C. H. June, B. L. Levine, et al. Anti-CD3/Anti-CD28 Bead Stimulation Overcomes CD3 Unresponsiveness in Patients With Head and Neck Squamous Cell Carcinoma Arch Otolaryngol Head Neck Surg, April 1, 2000; 126(4): 473 - 479. [Abstract] [Full Text] [PDF]
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D. L. Martin, C. L. King, E. Pearlman, E. Strine, and F. P. Heinzel IFN-{gamma} Is Necessary But Not Sufficient for Anti-CD40 Antibody-Mediated Inhibition of the Th2 Response to Schistosoma mansoni Eggs J. Immunol., January 15, 2000; 164(2): 779 - 785. [Abstract] [Full Text] [PDF]
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M. G. Chiaramonte, M. Hesse, A. W. Cheever, and T. A. Wynn CpG Oligonucleotides Can Prophylactically Immunize Against Th2-Mediated Schistosome Egg-Induced Pathology by an IL-12-Independent Mechanism J. Immunol., January 15, 2000; 164(2): 973 - 985. [Abstract] [Full Text] [PDF]
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M. Vukmanovic-Stejic, B. Vyas, P. Gorak-Stolinska, A. Noble, and D. M. Kemeny Human Tc1 and Tc2/Tc0 CD8 T-cell clones display distinct cell surface and functional phenotypes Blood, January 1, 2000; 95(1): 231 - 240. [Abstract] [Full Text] [PDF]
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A. Elhofy and K. L. Bost Limited Interleukin-18 Response in Salmonella-Infected Murine Macrophages and in Salmonella-Infected Mice Infect. Immun., October 1, 1999; 67(10): 5021 - 5026. [Abstract] [Full Text] [PDF]
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E. N. Villegas, M. M. Elloso, G. Reichmann, R. Peach, and C. A. Hunter Role of CD28 in the Generation of Effector and Memory Responses Required for Resistance to Toxoplasma gondii J. Immunol., September 15, 1999; 163(6): 3344 - 3353. [Abstract] [Full Text] [PDF]
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 E. Martin-Orozco, H. Kobayashi, J. Van Uden, M.-D. Nguyen, R. S. Kornbluth, and E. Raz Enhancement of antigen-presenting cell surface molecules involved in cognate interactions by immunostimulatory DNA sequences Int. Immunol., July 1, 1999; 11(7): 1111 - 1118. [Abstract] [Full Text] [PDF]
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C. S. Subauste, M. Wessendarp, R. U. Sorensen, and L. E. Leiva CD40-CD40 Ligand Interaction Is Central to Cell-Mediated Immunity Against Toxoplasma gondii: Patients with Hyper IgM Syndrome Have a Defective Type 1 Immune Response That Can Be Restored by Soluble CD40 Ligand Trimer J. Immunol., June 1, 1999; 162(11): 6690 - 6700. [Abstract] [Full Text] [PDF]
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C.-Y. Wu, H. Maeda, C. Contursi, K. Ozato, and R. A. Seder Differential Requirement of IFN Consensus Sequence Binding Protein for the Production of IL-12 and Induction of Th1-Type Cells in Response to IFN-{gamma} J. Immunol., January 15, 1999; 162(2): 807 - 812. [Abstract] [Full Text] [PDF]
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S. Gurunathan, K. R. Irvine, C.-Y. Wu, J. I. Cohen, E. Thomas, C. Prussin, N. P. Restifo, and R. A. Seder CD40 Ligand/Trimer DNA Enhances Both Humoral and Cellular Immune Responses and Induces Protective Immunity to Infectious and Tumor Challenge J. Immunol., November 1, 1998; 161(9): 4563 - 4571. [Abstract] [Full Text] [PDF]
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S. Haraguchi, N. K. Day, R. P. Nelson Jr., P. Emmanuel, J. E. Duplantier, C. S. Christodoulou, and R. A. Good Interleukin 12 deficiency associated with recurrent infections PNAS, October 27, 1998; 95(22): 13125 - 13129. [Abstract] [Full Text] [PDF]
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 P. Zhou and R. A. Seder CD40 Ligand Is Not Essential for Induction of Type 1 Cytokine Responses or Protective Immunity after Primary or Secondary Infection With Histoplasma capsulatum J. Exp. Med., April 20, 1998; 187(8): 1315 - 1324. [Abstract] [Full Text] [PDF]
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