| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
*
Committee on Immunology, Department of Pathology, Division of Biological Sciences, University of Chicago, Chicago, IL; and
Division of Cytokine Biology, Food and Drug Administration, Bethesda, MD
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
and -ß) in
human T cell differentiation using anti-CD3 mAb and allogeneic, in
vitro-derived dendritic cells (DC) as APCs. DC were very efficient
activators of naive CD4+ T cells, providing necessary
costimulation and soluble factors to support Th1 differentiation and
expansion. Addition of IFN-ß to DC/T cell cultures resulted in
induction of T cell IL-10 production and inhibition of IFN-
,
TNF-, and LT secretion. Diminished T cell IFN- production
correlated with IFN-ß-mediated inhibition of the p40 chain of the
IL-12 heterodimer secreted by DC. Suppression of p40 IL-12 and IFN-
was not due to increased levels of IL-10 in these cultures, and
production of IFN- could be restored by exogenous IL-12. These data
indicate that type I IFNs inhibit DC p40 IL-12 expression, which is
required for development of IFN--producing CD4+ T cells.
Furthermore, when T cells were restimulated without IFN-ß, these
cells induced less p40 IL-12 from DC, suggesting that the functional
properties of T cells may regulate DC function. Thus, IFN-ß
inhibits both IL-12-dependent and independent Th1 cytokine production
and provides a mechanism for inhibition of IL-12-mediated immunity in
viral infections. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-induced MHC class II
expression and inhibition of cell proliferation (1, 3). These cytokines
have been used for treatment of viral infections including HIV-1 and
hepatitis C (4, 5), some types of cancer (6), and, most recently, for
multiple sclerosis (MS) (7). Our laboratory and others have shown that
IFN-ß share some biologic activities with IL-12. IL-12 and
IFN-ß inhibit Th2 development through blocking IL-4 secretion and
stimulate CD4+ T cells to produce IL-10 (8, 9, 10, 11). IL-12 and
IFN-ß also enhance the lytic ability of CTL and NK cells and have
anti-viral effects that are independent of their activity on NK
cells (12). Moreover, signaling through the IL-12 or IFN-ß
receptor results in tyrosine phosphorylation of TYK2 and
phosphorylation and DNA binding of both STAT3 and STAT4 in human
lymphocytes (13, 14), suggesting that signaling through the two
receptors activates common kinases and transcription factors. However,
unlike IL-12, IFN-ß suppress cell proliferation and cannot induce
Th1 differentiation in response to Ag (15).
Recent reports suggest that IL-12 and IFN-ß, in contrast to their
shared biologic properties, also mediate discrete components of viral
immunity and provide evidence that IFN-ß may negatively regulate
IL-12 expression in vivo (16, 17). IFN-ß promote NK cell blast
formation and cytotoxicity but do not support IL-12-dependent NK cell
IFN- production (12). In mice, production of IFN-ß in response
to lymphocytic choriomeningitis virus (LCMV) infection was found to
suppress IL-12 production, and administration of neutralizing
IFN-ß Abs resulted in detectable levels of IL-12 and IFN- (17).
These results indicate that the efficacy of the immune response to some
pathogens may be determined at the level of IFN-ß and IL-12
regulation.
To further define the roles of type I IFNs and IL-12 in Th development
we have developed an in vitro system for human CD4+ T cell
differentiation using DC, immobilized hOKT3, and purified naive T
cells. DC produce IL-12 and promote differentiation of CD4+
T cells that produce IFN- and do not secrete Th2 cytokines (18).
Using our in vitro differentiation system, we found that IFN-ß act
directly on T cells to inhibit TNF- and LT production while inducing
IL-10 expression. Furthermore, IFN-ß were found to inhibit T cell
IFN- production by blocking DC secretion of functional IL-12
heterodimer, an effect which is independent of IL-10. These data
indicate that type I IFNs regulate Th1 differentiation via two distinct
mechanisms in vitro.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
CD14+ blood-derived monocytes were isolated
from peripheral blood by counterflow centrifugal elutriation (19) and
frozen at 4 x 107 cells/ml. Cells were thawed as
needed and cultured in six-well tissue culture plates (Costar,
Cambridge, MA) at 3.3 x 106/ml in complete culture
media (RPMI 1640 (Life Technologies, Gaithersburg, MD) supplemented
with 10% FBS, 20 mM L-glutamine, 100 IU/ml penicillin, and
100 µg/ml streptomycin (BioWhittaker, Walkersville, MD)). IL-4 and
granulocyte-macrophage CSF (GM-CSF) (PharMingen, San Diego, CA) were
added to the culture at 30 ng/ml at day 1, day 4, and day 7 of the
culture. At day 5 of culture TNF- (PharMingen) was added at 100
U/ml. Cells were harvested on day 9 of culture with EDTA, washed twice
with Ca/Mg free PBS, and used immediately for FACS analysis and T cell
differentiation assays.
Isolation of CD4+, CD45RA+, CD45RO- T cells
Human PBMC from buffy coats of healthy anonymous donors (HIV-1 negative, hepatitis negative) (United Blood Service, Chicago, IL) were isolated by Ficoll gradient centrifugation. Resting CD4+CD45RA+CD45RO- T cells were obtained by negative selection with Abs and magnetic beads as described (20). CD45RA+ cells were 99% pure by FACScan analysis using mouse mAb: CD45RA-phycoerythrin (PE) (clone B-C15, Biosource, Camarillo, CA) and CD45RO-FITC (clone UCHL1, Caltag, South San Francisco, CA). Staining of cells with Abs was conducted according to standard procedures as previously described (20) and evaluated using a FACScan (Becton Dickinson, San Jose, CA).
Stimulation conditions
Naive CD4+ T cells (1 x 106)
were cultured in a volume of 2 ml of complete culture media for 48
h in 24-well plates (No. 3524, Costar) that had been coated overnight
at 4°C with 0.5 ml of 1 µg/ml humanized CD3 mAb OKT3 (hOKT3)
(CDR grafted on human IgG1 (21)) in PBS. Allogeneic DC were irradiated
and added as accessory cells at a concentration of 1 x
105 per well. At the beginning of each (re)stimulation,
different combinations of the following recombinant human (rh)
cytokines were added to the cultures as indicated: rhIL-12 (Hoffman-La
Roche, Nutley, NJ), and rhIL-10 (PharMingen), at 1 ng/ml; rhIFN-
(Biosource) and rhIFN-ß-1a (Biogen, Cambridge, MA) at 0.05 to 5
ng/ml; IFN-ß was used at 5 ng/ml in all experiments except where
indicated; and rhIFN- (Life Technologies) at 5 ng/ml. Neutralizing
Abs (IL-10, PharMingen; IL-12 (polyclonal goat anti-human
p70), Hoffman-La Roche) were used at a final concentration of 10
µg/ml. The following control Ig were used: MOPC21, mouse IgG1, and
goat IgG (No. 55486, Organon Teknika, Durham, NC). At the end of the
primary 48-h stimulation period, 1 ml of supernatant was collected from
each well and frozen at -70°C. Cells were subsequently resuspended
in the remaining supernatant and transferred to an uncoated six-well
plate (No. 3516, Costar), and 1 ml of fresh media was added. Plastic
adherent DC were not transferred to six-well plates. Seven days after
the initial stimulation (5 days after cells were transferred to
six-well plates), the cells were counted and restimulated with fresh DC
and cytokines/neutralizing mAb for 48 h in 24-well plates (No.
3524, Costar) that had been coated with hOKT3 in PBS. ELISAs were
performed on supernatants harvested from the second stimulation. In
some experiments, T cells were stimulated a third time without the
addition of exogenous cytokines (Fig. 8
).
|
mAb pairs (PharMingen) were used in sandwich ELISAs to measure
IL-4 (sensitivity 50 pg/ml), IL-5 (sensitivity 100 pg/ml), human and
viral IL-10 (sensitivity 400 pg/ml), TNF- (sensitivity 200 pg/ml),
LT (sensitivity 150 pg/ml), IFN- (sensitivity 400 pg/ml), p40 chain
of IL-12 heterodimer, and IL-13 (sensitivity 1 ng/ml). MaxiSorp 96-well
plates (Nunc Inc., Naperville, IL) were coated with capture mAbs (1–4
ng/ml) overnight at 4°C. The following day plates were washed and
blocked with 3% BSA in PBS at room temperature for 2 h. Plates
were subsequently washed, and standards and samples were added to wells
and incubated overnight at 4°C. Biotinylated secondary mAb (1–3
µg/ml), avidin-peroxidase (Sigma, St. Louis, MO) and ABTS (Sigma)
were used to quantify cytokine, as per the PharMingen protocol.
Exogenous type I IFNs were not found to inhibit detection of cytokine
in any of the ELISAs.
Statistical analysis
A one-way ANOVA was used to examine for significant effects of culture conditions on cell cytokine secretion. Variation among culture conditions was examined with a Fisher PLSD test.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
To study human CD4+ T cell differentiation we
have used mature DC generated in vitro using the modified protocol of
Sallusto and Lanzavecchia (22). Mature DC were generated by culture of
elutriated monocytes with granulocyte-macrophage-CSF, IL-4, and TNF-
and expressed typical dendritic morphology (data not shown). DC were
negative for CD14 and expressed CD1a, a DC-specific marker, and lost
expression of the monocytic marker CD14 (data not shown). These cells
also expressed ICAM-1, LFA-1, LFA-3, and MHC class I and II. CD40,
CD80, and CD86, costimulatory molecules involved in T cell activation,
were also highly expressed on DC.
Type I IFNs inhibit secretion of Th1-type cytokines
To characterize the role of DC in CD4+ T cell
differentiation, we stimulated naive CD4+ T cells with
immobilized hOKT3 and DC, and supernatants were harvested for cytokine
analysis. DC were not capable of inducing CD4+ T cell
production of IL-4, IL-5, IL-10, or IL-13 after two rounds of
stimulation (Fig. 1). However, T cells
did produce the Th1 cytokines IFN-, TNF-, and LT in response to
hOKT3 and DC stimulation. Addition of IFN- or IFN-ß to these
cultures resulted in a significant, dose-dependent inhibition of
Th1-type cytokine secretion and induced secretion of IL-10 (Fig. 2). Low doses of IFN-ß (0.5 and 0.05
ng/ml) had a significant effect on TNF- and LT secretion, while only
the higher 5 ng/ml dose significantly suppressed IFN- production and
gave optimal IL-10 production. These results suggest that DC are potent
APCs for activation of naive CD4+ T cells in vitro and that
type I IFNs inhibit Th1-type cytokine secretion.
|
|
One possible mechanism by which IFN-ß may inhibit
CD4+ T cell IFN- production is through suppression
of DC IL-12 secretion. To determine whether IFN-ß are involved in
the regulation of DC IL-12 expression we measured production of p40
chain of the IL-12 heterodimer. Expression of the p40 chain is tightly
regulated and expressed only in cells that make the functional p35/40
heterodimer (23). DC cultured with T cells and hOKT3 produced
significantly higher levels of p40 than DC on hOKT3 (Fig. 3). Addition of IFN-ß to DC/T cell
cultures resulted in a dramatic decrease in p40 expression that
corresponded with the diminished IFN- detected in these cultures.
Similar results were obtained using IFN- (data not shown).
Interestingly, we found that inhibition of p40 expression correlated
with increased levels of IL-10 (Fig. 4),
a cytokine which is known to negatively regulate IL-12 secretion (24).
To our knowledge, this is the first report demonstrating that
IFN-ß inhibits expression of inducible p40 IL-12 expression in
human DC.
|
|
, TNF-, and LT expression is
independent of IL-10
IL-10 is an inhibitory cytokine that has been shown to suppress T
cell cytokine secretion (25). To determine whether IFN-ß directly
suppresses cytokine production or does so by inducing IL-10, we added
IFN-ß to cultures containing neutralizing anti-IL-10 mAb.
Cultures containing control Ig produced normal levels of p40 IL-12,
IFN-, TNF-, and LT (Fig. 5).
Addition of IL-10 slightly reduced the amount of p40 IL-12 detected, as
has been reported (24). However, levels of each cytokine were
significantly lower in cultures containing either IFN-ß alone or
IFN-ß/anti-IL-10 mAb, when compared with cultures containing
control Ig (Fig. 5). Cytokine expression was not increased by
anti-IL-10 mAb, suggesting that IL-10 is not involved in
IFN-ß-mediated inhibition of p40 IL-12, IFN-, TNF-, and LT
production. Anti-IL-10 mAb were capable of neutralizing IFN-ß-induced
IL-10 as determined by ELISA (data not shown). Although IFN-ß-induced
IL-10 may be a contributing factor in the inhibition of DC p40 IL-12
and CD4+ T cell cytokine production, our data
demonstrate that type I IFNs inhibit cytokine secretion through a
mechanism that is largely independent of IL-10 (Fig. 5) (10).
|
ß inhibits secretion of functional IL-12 heterodimer
There are two possible mechanisms by which IFN-ß might
inhibit IFN- production: 1) by decreasing secretion of functional
IL-12, or 2) by acting directly on CD4+ T cells to
modulate IFN-, with diminished p40 IL-12 expression occurring as a
secondary effect. To address these two possibilities, we added both
IL-12 and IFN-ß to cultures to determine whether exogenous IL-12
could compensate for IFN-ß-mediated suppression of endogenous IL-12
production. Addition of IL-12 to cultures containing DC,
CD4+ T cells, and hOKT3 enhanced expression of IFN-,
when compared with cultures without exogenous IL-12 (Fig. 6). IL-12 plus IFN-ß had no effect on
levels of IFN- detected but significantly decreased production of
the p40 chain of IL-12, suggesting that exogenous IL-12 could
compensate for diminished endogenous IL-12 heterodimer secreted in
response to IFN-ß. In addition, anti-IL-12 Abs and IFN-ß had
similar effects in strongly inhibiting expression of p40 IL-12 and
IFN-. These results provide further evidence that IFN-ß
inhibits CD4+ T cell secretion of IFN- by blocking DC
production of functional IL-12 protein, which can be overcome by
addition of exogenous IL-12. Although IFN-ß appears to influence
priming for IFN- primarily through its regulation of DC IL-12
secretion, we cannot rule out a direct role for IFN-ß in IFN- gene
expression.
|
ß
DC have been shown to produce IL-12 and to direct the
differentiation of Th1 cells in vitro (18, 26). To further characterize
the role of DC in IL-12-independent Th1 differentiation, we compared
the effect of neutralizing anti-IL-12 Abs with IFN-ß on Th1
development in vitro. Anti-IL-12 Abs significantly inhibited T cell
priming for IFN- production but had no effect on TNF- or LT (Fig. 7). In contrast, IFN-ß inhibited
production of IFN-, TNF-, and LT. These results suggest that
IL-12 is not necessary for differentiation of TNF-- and LT-producing
CD4+ T cells in vitro and that IFN-ß acts on both
DC and T cells to inhibit secretion of proinflammatory cytokines.
|
ß secrete less TNF- and LT
The data presented above may have at least two interpretations:
type I IFNs either inhibit differentiation of Th1-like T cells or
promote differentiation of cells expressing low levels of Th1
cytokines. To distinguish these two possibilities, we compared the
cytokine secretion profiles of T cells stimulated twice in the presence
or absence of IFN-ß and then restimulated a third time without
IFN-ß. T cells stimulated two times in the presence of IFN-ß
produced less TNF- and LT during the third stimulation than control
cells stimulated in the absence of IFN-ß (Fig. 8
). Interestingly, T cells cultured with
IFN-ß induced less p40 IL-12 secretion from DC than T cells
stimulated in the absence of IFN-ß, suggesting that the functional
properties of the T cell regulate DC cytokine profiles. Suboptimal
induction of p40 IL-12 from DC in these cultures may be due to
lower levels of T cell IFN- production. We found that neutralizing
IFN- mAbs inhibited p40 IL-12 production by approximately 50%,
suggesting a role for IFN- in p40 IL-12 expression, as previously
reported (27) (data not shown). Finally, cells cultured with IFN-ß
expressed a similar activated/memory phenotype (CD45RO+,
CD45RA-) and up-regulation of activation markers (CD25,
CD69) as cells differentiated without IFN-ß (data not shown). This
suggests that type I IFNs do not inhibit differentiation but promote
development of Th1 cells that have a limited capacity to secrete
TNF- and LT and whose ability to produce IFN- may be dependent
upon the type of APC.
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
, cannot drive either Th1 or Th2
development (33). IL-12 is a critical factor in generation of
IFN--producing T cells (34), but type I IFNs are not sufficient to
promote IFN- production (9, 10, 15). Using an EBV-transformed B cell
line, JY, as APC, we found that IFN-ß had little effect on
differentiation of IFN--producing CD4+ T cells but
inhibited TNF- and LT production (10). Here we have used DC to
determine how type I IFNs influence Th development through modulating
APC function. DC are very efficient in activation of naive T cells due
to high expression of MHC class I and II molecules as well as
costimulatory molecules, and production of cytokines that support T
cell maturation (35). Immature DC capture large amounts of Ag through
both macropinocytosis and receptor-mediated pathways (36). Bacterial
products and inflammatory cytokines, such as TNF- and IL-1, lead to
DC maturation and migration to regional lymph nodes, which is
accompanied by enhanced costimulatory capacity and loss of endocytic
activity (36, 37). Our initial experiments using DC confirmed previous
findings that IFN-ß suppresses TNF- and LT production by
CD4+ T cells but also demonstrated that IFN-ß blocks
priming for IFN- secretion. This inhibition of IFN- production
directly correlated with decreased DC p40 IL-12 secretion. In addition,
IFN- production could be restored in the presence of IFN-ß by
addition of exogenous IL-12, suggesting that type I IFNs inhibit
secretion of functional IL-12 heterodimer from DC.
Our results differ from those of several laboratories that have
reported that IFN- increases levels of IFN- mRNA and protein
(38, 39, 40). These studies have used populations of CD4+ T
cells containing both naive and previously activated cells. Enhanced
IFN- mRNA and protein levels in these experiments were probably due
to inhibition of IL-4 secretion from differentiated CD4+ T
cells, which in turn resulted in higher IFN- rather than a direct
effect of IFN- on priming for IFN- production. This is supported
by findings that IFN-ß inhibits production of IL-4 and IL-5 (9, 10, 41). Collectively, these data indicate that IFN-ß can promote
outgrowth of Th1 cells by suppressing production of Th2 cytokines that
inhibit IFN- secretion and indicate that type I IFNs do not directly
inhibit or promote CD4+ T cell production of IFN- but
influence differentiation of IFN--producing CD4+ T cells
by blocking DC IL-12.
Recent studies using two murine models have shown that IFN-ß
produced in response to viral pathogens determine the nature of the
immune response. Murine cytomegalovirus (MCMV) infection of C57BL/6
mice results in IL-12 production and NK cell IFN- production, while
LCMV infection does not induce detectable levels of IL-12 or IFN-
(42). This suggests that IL-12 responses are regulated differently by
these two viruses so as to create distinct cytokine environments during
early stages of infection. Cousens et al. (17) have shown that
detectable levels of IL-12 can be found in IFN-ßR knockout mice
during LCMV infection (17). In addition, splenocytes isolated from
LCMV-infected mice could produce IL-12 in vitro, which was inhibited by
exogenous IFN-. This report is the first direct evidence that
IFN-ß produced in response to viral infection suppress IL-12
production in vivo.
Although IL-10 is produced late in the immune response (25), after
IL-12 induction, we initially could not rule out a role for IL-10 in
IFN-ß-mediated IL-12 suppression. Subsequently, we found that
inhibition of DC IL-12 was not due to enhanced T cell production of
IL-10, since neutralizing anti-IL-10 mAbs did not block
IFN-ß-mediated inhibition of p40 IL-12. Furthermore, exogenous IL-10
did not suppress p40 IL-12 to the levels observed with IFN-ß,
suggesting that IFN-ß inhibits IL-12 through a mechanism that is
largely independent of IL-10. IL-10 serves as a negative regulator of
IL-12-mediated responses and directly inhibits IL-12 production (24, 43). The importance of IL-10 in regulating persistent IL-12-driven
responses was shown in IL-10 knockout mice infected with
Toxoplasma gondii, in which overproduction of IL-12 resulted
in death (44). It is likely, however, that endogenous IL-10 and
IFN-ß act at different points in an immune response such that
IFN-ß may block the initiation of IL-12-mediated responses, while
IL-10 down-regulates ongoing IL-12-mediated responses.
Since IFN- has also been shown to regulate IL-12 production in
macrophages (27), we considered the possibility that IFN-ß may
inhibit p40 IL-12 by blocking IFN- production. We found that, when
CD4+ T cells were activated with hOKT3 and DC, neutralizing
IFN- mAbs diminished p40 IL-12 secretion by approximately 50% (data
not shown). However, when mAbs against CD40 were used to stimulate DC
p40 IL-12 secretion, IFN-ß inhibited p40 IL-12 by more than 80%
(B.L. McRae, manuscript in preparation). These results suggest that
IFN- is not required for p40 IL-12 production and that IFN-ß can
inhibit DC p40 IL-12 independent of its effects on T cell function.
Components of innate immunity and bacterial products (i.e., IFNs,
TNF-, LPS) can regulate APC maturation and function. However, the
role of these factors in directing acquired immunity is unclear. DC
produce IFN- in response to HIV-1 infection in vitro (2), and high
titers of IFN- can be detected in the plasma of HIV-1-infected
individuals during both early and late phases of disease (45). IFN-
can decrease viremia and boost levels of circulating CD4+ T
cells in HIV-1-infected individuals, but there is evidence that HIV-1
isolates resistant to the anti-viral effects of IFN- are
frequently found in late stages of disease (46). This raises the
possibility that IFN- actually contributes to the general
immunosuppression characteristic of AIDS by suppressing IL-12
production. In fact, it is reported that PBMC from HIV-infected
individuals are less capable of producing IL-12 than cells from
uninfected donors (47). Furthermore, DC activated in vitro with HIV-1
produce IFN- protein and IL-12 mRNA but not IL-12 protein,
suggesting that IFN- may act in an autocrine fashion to suppress
IL-12. Measles virus infection of human DC and monocytes was also found
to decrease IL-12 secretion (48, 49), although a role for IFN-ß in
measles-mediated immunosuppression has not been confirmed. Other
studies will be required to determine whether the inability to produce
IL-12 during the course of measles and HIV-1 infection and subsequent
susceptibility to infection are directly related to the suppressive
effects of IFN-ß.
Apart from their antiviral properties, type I IFNs have been effective in the treatment of other diseases, such as multiple sclerosis (MS). There is a growing body of evidence suggesting that autoreactive T cells play a role in MS (50) and that IFN-ß treatment may reduce the exacerbation rate by disrupting leukocyte trafficking (51). This interpretation is supported by recent findings in an experimentally induced disease model that IFN-ß decreases extravasation of mononuclear cells into the central nervous system (CNS) (52). We have previously demonstrated that IFN-ß regulates both L-selectin and cutaneous lymphocyte-associated Ag (CLA) expression (10). Data presented here may indicate that inhibition of IL-12, another cytokine shown to modulate homing phenotype during T cell activation (53), influences trafficking patterns of autoreactive lymphocytes. In addition, IFN-ß inhibits T cell expression of a 92-kDa matrix metalloprotease, MMP-9, which prevents lymphocyte migration in vitro (54, 55). Thus, IFN-ß probably has multiple effects on immune cells in vivo, including regulation of cytokine production and leukocyte trafficking.
In summary, we have demonstrated that CD4+ T cells
differentiated with hOKT3 and DC in the presence of IFN-ß produce
IL-10 but secrete less IFN-, TNF-, and LT than cells stimulated
in the absence of IFN-ß. The lack of IFN- produced by cells
cultured with IFN-ß was due to impaired DC IL-12 production and
could be overcome by addition of exogenous IL-12. T cells stimulated in
the presence of IFN-ß and then restimulated without IFN-ß
produced significantly less cytokine than cells differentiated in the
absence of IFN-ß. This may indicate a stable influence on Th cell
differentiation, which may not be properly reflected in these studies
because of the relative heterogeneity of the Th cells. Alternatively,
we cannot rule out the possibility that IFN-ß may also directly
regulate TNF- and LT gene expression. T cell recognition of Ag/MHC
complexes on APC have been regarded as one-way interactions resulting
in T cell activation. However, our data and those from other
laboratories (36) suggest that DC function is regulated by T cells; T
cells differentiated in the absence, or in low levels, of IL-12 were
less capable of stimulating IL-12 production from DC. These results
indicate that the functional properties of activated/memory
CD4+ T cells regulate APC function and stress the
importance of using physiologically relevant APCs when studying T cell
differentiation. Since CD40-CD40L interaction has been demonstrated to
induce IL-12 production in DC (56), we have initiated experiments to
address the role of this receptor system in IFN-ß-mediated IL-12
suppression. Preliminary results suggest that IFN-ß do not
diminish expression of CD40L on CD4+ T cells (data not
shown). Further studies will be necessary to determine whether
down-regulation of CD40 expression on DC results in less IL-12
production during T cell activation.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Gijs A. van Seventer, Committee on Immunology and Department of Pathology, Division of Biological Sciences, University of Chicago, 5841 South Maryland Avenue, Room J541A, MC1089, Chicago, IL 60637. E-mail address:
3 Abbreviations used in this paper: DC, dendritic cell; LT, lymphotoxin; LCMV, lymphocytic choriomeningitis virus; hOKT3, humanized CD3 mAb OKT3; h, human; PLSD, protected least significant difference.
Received for publication August 19, 1997. Accepted for publication January 6, 1998.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
(IFN-) production during differentiation of human T helper (Th) cells and transient IFN- production in established Th2 cell clones. J. Exp. Med. 179:1273. increases the frequency of interferon gamma-producing human CD4+ T cells. J. Exp. Med. 178:1655.This article has been cited by other articles:
|
|
 |
|
  C. D. Conrady, M. Thapa, T. Wuest, and D. J. J. Carr Loss of Mandibular Lymph Node Integrity Is Associated with an Increase in Sensitivity to HSV-1 Infection in CD118-Deficient Mice J. Immunol., March 15, 2009; 182(6): 3678 - 3687. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Sanna, Y. Huang, G Arru, M. Fois, H Link, G Rosati, and S Sotgiu Multiple sclerosis: reduced proportion of circulating plasmacytoid dendritic cells expressing BDCA-2 and BDCA-4 and reduced production of IL-6 and IL-10 in response to herpes simplex virus type 1 Multiple Sclerosis, November 1, 2008; 14(9): 1199 - 1207. [Abstract] [PDF]
|
|
|
|
 |
|
 S. Munir, C. Le Nouen, C. Luongo, U. J. Buchholz, P. L. Collins, and A. Bukreyev Nonstructural Proteins 1 and 2 of Respiratory Syncytial Virus Suppress Maturation of Human Dendritic Cells J. Virol., September 1, 2008; 82(17): 8780 - 8796. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Gerlini, G. Mariotti, A. Chiarugi, P. Di Gennaro, R. Caporale, A. Parenti, L. Cavone, A. Tun-Kyi, F. Prignano, R. Saccardi, et al. Induction of CD83+CD14+ Nondendritic Antigen-Presenting Cells by Exposure of Monocytes to IFN-{alpha} J. Immunol., September 1, 2008; 181(5): 2999 - 3008. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Qiu, Y. Fan, A. G. Joyee, S. Wang, X. Han, H. Bai, L. Jiao, N. Van Rooijen, and X. Yang Type I IFNs Enhance Susceptibility to Chlamydia muridarum Lung Infection by Enhancing Apoptosis of Local Macrophages J. Immunol., August 1, 2008; 181(3): 2092 - 2102. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M Krakauer, P Sorensen, M Khademi, T Olsson, and F Sellebjerg Increased IL-10 mRNA and IL-23 mRNA expression in multiple sclerosis: interferon-{beta} treatment increases IL-10 mRNA expression while reducing IL-23 mRNA expression Multiple Sclerosis, June 1, 2008; 14(5): 622 - 630. [Abstract] [PDF]
|
|
|
|
 |
|
 M. C. Lebre, S. L. Jongbloed, S. W. Tas, T. J.M. Smeets, I. B. McInnes, and P. P. Tak Rheumatoid Arthritis Synovium Contains Two Subsets of CD83-DC-LAMP- Dendritic Cells with Distinct Cytokine Profiles Am. J. Pathol., April 1, 2008; 172(4): 940 - 950. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. A. Byrnes, D.-Y. Li, K. Park, D. Thompson, C. Mocilnikar, P. Mohan, J. P. Molleston, M. Narkewicz, H. Zhou, S. F. Wolf, et al. Modulation of the IL-12/IFN-{gamma} axis by IFN-{alpha} therapy for hepatitis C J. Leukoc. Biol., March 1, 2007; 81(3): 825 - 834. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Longman, D. Braun, S. Pellegrini, C. M. Rice, R. B. Darnell, and M. L. Albert Dendritic-cell maturation alters intracellular signaling networks, enabling differential effects of IFN-{alpha}/{beta} on antigen cross-presentation Blood, February 1, 2007; 109(3): 1113 - 1122. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Teige, Y. Liu, and S. Issazadeh-Navikas IFN-beta Inhibits T Cell Activation Capacity of Central Nervous System APCs J. Immunol., September 15, 2006; 177(6): 3542 - 3553. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Fahey, R. A. Robins, K. B. Kindle, D. M. Heery, and C. S. Constantinescu Effects of glucocorticoids on STAT4 activation in human T cells are stimulus-dependent J. Leukoc. Biol., July 1, 2006; 80(1): 133 - 144. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Severa, M. E. Remoli, E. Giacomini, J. Ragimbeau, R. Lande, G. Uze, S. Pellegrini, and E. M. Coccia Differential responsiveness to IFN-{alpha} and IFN-{beta} of human mature DC through modulation of IFNAR expression J. Leukoc. Biol., June 1, 2006; 79(6): 1286 - 1294. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Ito, I. Kawamura, C. Kohda, K. Tsuchiya, T. Nomura, and M. Mitsuyama Seeligeriolysin O, a protein toxin of Listeria seeligeri, stimulates macrophage cytokine production via Toll-like receptors in a profile different from that induced by other bacterial ligands Int. Immunol., December 1, 2005; 17(12): 1597 - 1606. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Dikopoulos, A. Bertoletti, A. Kroger, H. Hauser, R. Schirmbeck, and J. Reimann Type I IFN Negatively Regulates CD8+ T Cell Responses through IL-10-Producing CD4+ T Regulatory 1 Cells J. Immunol., January 1, 2005; 174(1): 99 - 109. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. C. Zang, S. M Skinner, R. R Robinson, S. Li, V. M Rivera, G. J Hutton, and J. Z Zhang Regulation of differentiation and functional properties of monocytes and monocyte-derived dendritic cells by interferon beta in multiple sclerosis Multiple Sclerosis, October 1, 2004; 10(5): 499 - 506. [Abstract] [PDF]
|
|
|
|
|
|
R. Yang, F. M. Murillo, K.-Y. Lin, W. H. Yutzy IV, S. Uematsu, K. Takeda, S. Akira, R. P. Viscidi, and R. B. S. Roden Human Papillomavirus Type-16 Virus-Like Particles Activate Complementary Defense Responses in Key Dendritic Cell Subpopulations J. Immunol., August 15, 2004; 173(4): 2624 - 2631. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. Morrison, C. B. Wilson, M. Ray, and P. H. Correll Macrophage-Stimulating Protein, the Ligand for the Stem Cell-Derived Tyrosine Kinase/RON Receptor Tyrosine Kinase, Inhibits IL-12 Production by Primary Peritoneal Macrophages Stimulated with IFN-{gamma} and Lipopolysaccharide J. Immunol., February 1, 2004; 172(3): 1825 - 1832. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Nagai, O. Devergne, T. F. Mueller, D. L. Perkins, J. M. van Seventer, and G. A. van Seventer Timing of IFN-{beta} Exposure during Human Dendritic Cell Maturation and Naive Th Cell Stimulation Has Contrasting Effects on Th1 Subset Generation: A Role for IFN-{beta}-Mediated Regulation of IL-12 Family Cytokines and IL-18 in Naive Th Cell Differentiation J. Immunol., November 15, 2003; 171(10): 5233 - 5243. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
I. Teige, A. Treschow, A. Teige, R. Mattsson, V. Navikas, T. Leanderson, R. Holmdahl, and S. Issazadeh-Navikas IFN-{beta} Gene Deletion Leads to Augmented and Chronic Demyelinating Experimental Autoimmune Encephalomyelitis J. Immunol., May 1, 2003; 170(9): 4776 - 4784. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Krug, S. Rothenfusser, S. Selinger, C. Bock, M. Kerkmann, J. Battiany, A. Sarris, T. Giese, D. Speiser, S. Endres, et al. CpG-A Oligonucleotides Induce a Monocyte-Derived Dendritic Cell-Like Phenotype That Preferentially Activates CD8 T Cells J. Immunol., April 1, 2003; 170(7): 3468 - 3477. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Jinushi, T. Takehara, T. Kanto, T. Tatsumi, V. Groh, T. Spies, T. Miyagi, T. Suzuki, Y. Sasaki, and N. Hayashi Critical Role of MHC Class I-Related Chain A and B Expression on IFN-{alpha}-Stimulated Dendritic Cells in NK Cell Activation: Impairment in Chronic Hepatitis C Virus Infection J. Immunol., February 1, 2003; 170(3): 1249 - 1256. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. P. M. Brok, M. van Meurs, E. Blezer, A. Schantz, D. Peritt, G. Treacy, J. D. Laman, J. Bauer, and B. A. 't Hart Prevention of Experimental Autoimmune Encephalomyelitis in Common Marmosets Using an Anti-IL-12p40 Monoclonal Antibody J. Immunol., December 1, 2002; 169(11): 6554 - 6563. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. B. Nguyen, W. T. Watford, R. Salomon, S. R. Hofmann, G. C. Pien, A. Morinobu, M. Gadina, J. J. O'Shea, and C. A. Biron Critical Role for STAT4 Activation by Type 1 Interferons in the Interferon-gamma Response to Viral Infection Science, September 20, 2002; 297(5589): 2063 - 2066. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Natarajan and J. J. Bright Curcumin Inhibits Experimental Allergic Encephalomyelitis by Blocking IL-12 Signaling Through Janus Kinase-STAT Pathway in T Lymphocytes J. Immunol., June 15, 2002; 168(12): 6506 - 6513. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Trobonjaca, A. Kroger, D. Stober, F. Leithauser, P. Moller, H. Hauser, R. Schirmbeck, and J. Reimann Activating Immunity in the Liver. II. IFN-{beta} Attenuates NK Cell-Dependent Liver Injury Triggered by Liver NKT Cell Activation J. Immunol., April 15, 2002; 168(8): 3763 - 3770. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Luft, P. Luetjens, H. Hochrein, T. Toy, K.-A. Masterman, M. Rizkalla, C. Maliszewski, K. Shortman, J. Cebon, and E. Maraskovsky IFN-{alpha} enhances CD40 ligand-mediated activation of immature monocyte-derived dendritic cells Int. Immunol., April 1, 2002; 14(4): 367 - 380. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G.-X. Zhang, H. Xu, M. Kishi, D. Calida, and A. Rostami The Role of IL-12 in the Induction of Intravenous Tolerance in Experimental Autoimmune Encephalomyelitis J. Immunol., March 1, 2002; 168(5): 2501 - 2507. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Dalod, T. P. Salazar-Mather, L. Malmgaard, C. Lewis, C. Asselin-Paturel, F. Briere, G. Trinchieri, and C. A. Biron Interferon {alpha}/{beta} and Interleukin 12 Responses to Viral Infections: Pathways Regulating Dendritic Cell Cytokine Expression In Vivo J. Exp. Med., February 19, 2002; 195(4): 517 - 528. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Buelens, E. J. Bartholome, Z. Amraoui, M. Boutriaux, I. Salmon, K. Thielemans, F. Willems, and M. Goldman Interleukin-3 and interferon beta cooperate to induce differentiation of monocytes into dendritic cells with potent helper T-cell stimulatory properties Blood, February 1, 2002; 99(3): 993 - 998. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Lehner, T. Felzmann, K. Clodi, and W. Holter Type I interferons in combination with bacterial stimuli induce apoptosis of monocyte-derived dendritic cells Blood, August 1, 2001; 98(3): 736 - 742. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Wysocka, S. Robertson, H. Riemann, J. Caamano, C. Hunter, A. Mackiewicz, L. J. Montaner, G. Trinchieri, and C. L. Karp IL-12 Suppression During Experimental Endotoxin Tolerance: Dendritic Cell Loss and Macrophage Hyporesponsiveness J. Immunol., June 15, 2001; 166(12): 7504 - 7513. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. K. Levings, R. Sangregorio, F. Galbiati, S. Squadrone, R. de Waal Malefyt, and M.-G. Roncarolo IFN-{{alpha}} and IL-10 Induce the Differentiation of Human Type 1 T Regulatory Cells J. Immunol., May 1, 2001; 166(9): 5530 - 5539. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. H. Libraty, S. Pichyangkul, C. Ajariyakhajorn, T. P. Endy, and F. A. Ennis Human Dendritic Cells Are Activated by Dengue Virus Infection: Enhancement by Gamma Interferon and Implications for Disease Pathogenesis J. Virol., April 15, 2001; 75(8): 3501 - 3508. [Abstract] [Full Text]
|
|
|
|
|
|
P. Harle, S. Noisakran, and D. J. J. Carr The Application of a Plasmid DNA Encoding IFN-{{alpha}}1 Postinfection Enhances Cumulative Survival of Herpes Simplex Virus Type 2 Vaginally Infected Mice J. Immunol., February 1, 2001; 166(3): 1803 - 1812. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Zou, J. Borvak, F. Marches, S. Wei, P. Galanaud, D. Emilie, and T. J. Curiel Macrophage-Derived Dendritic Cells Have Strong Th1-Polarizing Potential Mediated by {beta}-Chemokines Rather Than IL-12 J. Immunol., October 15, 2000; 165(8): 4388 - 4396. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Ma and L. J. Montaner Proinflammatory response and IL-12 expression in HIV-1 infection J. Leukoc. Biol., September 1, 2000; 68(3): 383 - 390. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. L. McRae, T. Nagai, R. T. Semnani, J. M. van Seventer, and G. A. van Seventer Interferon-alpha and -beta inhibit the in vitro differentiation of immunocompetent human dendritic cells from CD14+ precursors Blood, July 1, 2000; 96(1): 210 - 217. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. A. Kallmann, V. Hummel, T. Lindenlaub, K. Ruprecht, K. V. Toyka, and P. Rieckmann Cytokine-induced modulation of cellular adhesion to human cerebral endothelial cells is mediated by soluble vascular cell adhesion molecule-1 Brain, April 1, 2000; 123(4): 687 - 697. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Hiroishi, T. Tuting, and M. T. Lotze IFN-{alpha}-Expressing Tumor Cells Enhance Generation and Promote Survival of Tumor-Specific CTLs J. Immunol., January 15, 2000; 164(2): 567 - 572. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. L. McRae, B. A. Beilfuss, and G. A. v. Seventer IFN-{beta} Differentially Regulates CD40-Induced Cytokine Secretion by Human Dendritic Cells J. Immunol., January 1, 2000; 164(1): 23 - 28. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Fallarino and T. F. Gajewski Cutting Edge: Differentiation of Antitumor CTL In Vivo Requires Host Expression of Stat1 J. Immunol., October 15, 1999; 163(8): 4109 - 4113. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kanto, N. Hayashi, T. Takehara, T. Tatsumi, N. Kuzushita, A. Ito, Y. Sasaki, A. Kasahara, and M. Hori Impaired Allostimulatory Capacity of Peripheral Blood Dendritic Cells Recovered from Hepatitis C Virus-Infected Individuals J. Immunol., May 1, 1999; 162(9): 5584 - 5591. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.G. Begley and N.A. Nicola Resolving Conflicting Signals: Cross Inhibition of Cytokine Signaling Pathways Blood, March 1, 1999; 93(5): 1443 - 1447. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
