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and TNF- Are Required for IL-12-Induced Development of Th1 Cells Producing High Levels of IFN-
in BALB/c But Not C57BL/6 Mice1
*
Department of Immunobiology, DNAX Research Institute of Molecular and Cellular Biology, Inc., Palo Alto, CA 94303;
Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110; and
Department of Pathobiology, University of Pennsylvania, Philadelphia, PA 19104
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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upon restimulation with splenic APC. The present
study shows that using dendritic cells to present Ag upon restimulation
reveals a requirement for additional cofactors, including IL-1
and
TNF-, which were provided by spleen cells but not dendritic cells.
Furthermore, these cofactors are required for optimal IL-12-induced Th1
development in BALB/c but not C57BL/6 mice. This differential
requirement for such cofactors in IL-12-driven Th1 development may play
a role in genetic predisposition to Th1 or Th2 responses to infectious
agents. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, and
lymphotoxin (TNF-ß) and promote cell-mediated effector responses,
whereas Th2 cells produce IL-4, IL-5, IL-6, and IL-10, cytokines that
can augment humoral responses and stimulate mast cells and eosinophils
to promote allergic-type responses (1, 2, 3, 4). Early events in an immune
response stimulate the production of cytokines (5, 6, 7, 8, 9, 10, 11), which in turn,
direct the subsequent development of Th subsets. These events are
strongly dictated by the type of Ag/micro-organism invading a host as
well as by the genetic background of the host. It is likely that the
dose and route of immunization with Ag may also be determining factors
(3, 12, 13, 14).
The most clearly defined factors determining Th1 and Th2
differentiation are cytokines present at the initiation of the immune
response, at the stage of activation through the TCR (3, 5, 6, 7, 8, 9, 10, 11, 12, 13).
Bacterial infection leads to the activation of macrophages and
subsequently NK cells. This innate immune response results in the
production of IL-12 and IFN- (8, 15), which then drive the
development of Th1-type cells from naive Ag-specific
CD4+ T cells, leading to the production of high levels
of IFN- (8, 10, 11, 15). Conversely, IL-4 induces a Th2 or
allergic/humoral-type immune response that can often lead to
down-regulation of cell-mediated immunity (5, 6, 7, 9).
Previously, we reported conditions for inducing a Th1 phenotype using
the DO11.10 TCR-ß-transgenic mouse (BALB/c genetic background) in
which 80% of CD4+ T cells express a unique TCR specific
for a peptide of OVA (8, 16, 17). Addition of IL-12 to primary cultures
of CD4+ T cells stimulated with OVA and splenocytes or
dendritic cells resulted in the development of a Th1 phenotype with the
capacity to secrete high levels of IFN- (8, 17, 18) upon
restimulation with splenic APC. The present study shows that additional
cofactors, including IL-1 and TNF- are required for optimal
IL-12-induced Th1 development in BALB/c but not C57BL/6 mice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mice transgenic for a TCR-ß recognizing
OVA323–339 (D011.10; BALB/c genetic background) (16)
were selected at 6 to 8 wk of age by staining peripheral blood
leukocytes with the anti-clonotype mAb KJ1-26 (19). Mice transgenic
for a TCR-ß recognizing a peptide of hen egg lysozyme,
HEL74–88,3 were
selected at 6 to 8 wk of age by PCR analysis of DNA obtained from ear
punches, analyzed for the rearranged transgenic TCR (S. B. Hartley
et al., manuscript in preparation). All transgenic mice used in these
experiments were heterozygous for the integration of the TCR
ß-chains. BALB/c mice between 6 and 10 wk of age were purchased
from Simonsen Laboratories (Gilroy, CA). C57BL/6 mice between 6 and 10
wk of age were purchased from The Jackson Laboratory (Bar Harbor,
ME).
Culture medium, cytokines, Abs, and Ags
RPMI 1640 (JR Scientific, Inc., Woodland CA) supplemented with 10% FCS (JR Scientific), 2-ME (0.05 mM; Sigma), L-glutamine (2 mM), penicillin (100 U/ml), streptomycin (100 µg/ml), HEPES buffer (10 mM), and sodium pyruvate (1 mM) was used as culture medium. For dendritic cell isolations, RPMI 1640 Dutch modification (Life Technologies, Paisley, Scotland) was used with glutamine, 2-ME (0.05 mM; Sigma), FCS, penicillin, and streptomycin as described above.
Recombinant mouse cytokines were as follows: IFN- (Genzyme,
Cambridge, MA), IL-4 (Dr. S. Menon, DNAX), TNF- (Genzyme), and
IL-1 (a gift from Peter Lomedico, Roche, Nutley, NJ). Recombinant
mouse IL-12 was obtained from PharMingen (San Diego, CA) and was as
described previously (20, 21).
Purified rat anti-mouse IL-4, 11B11, (22), anti-TNF-
(XT/22), and anti-IFN- (XMG1.2) plus isotype-matched controls
were supplied by J. Abrams (23) (DNAX). Anti-mouse IL-1 (ALF 161)
and anti-mouse IL-1 receptor mAb (JAMA) along with isotype-matched
controls (B122 and L2, respectively) were gifts from Dr. E. Unanue,
Washington University (St. Louis, MO) (24, 25, 26). Anti-IL-12 mAbs
(C17.8.20) were described by Wysocka and Trinchieri (27). Other Abs
used included anti-mouse Mac-1 (M1/70, Caltag, San Francisco, CA);
hamster anti-mouse N418 (American Type Culture Collection,
Rockville, MD) (28); biotinylated anti-mouse CD8, B220, GR-1,
anti-Mac-1, and anti-I-Ad (PharMingen); and
anti-mouse CD4 FITC (or phycoerythrin) and anti-L-selectin FITC
(PharMingen). mAbs for ELISA, including anti-IL-4 and IFN-
reagents, were purified from serum-free hybridoma supernatants as
previously described (23).
The antigenic peptides from chicken, OVA323–339, and HEL74–88 were synthesized by Biosynthesis (Lewisville, TX).
Preparation of T cells and APCs
CD4+ T cells were enriched by negative
selection using magnetic activated cell sorting with a mixture of
biotinylated anti-CD8, anti-I-Ad, anti-B220,
anti-GR-1, and anti-Mac-1 Abs (Miltenyi, Sunnyvale, CA).
CD4+ T cells, enriched by negative selection using magnetic
activated cell sorting were further purified using a
FACStarPlus flow cytometer (Becton Dickinson, Mountain
View, CA) to achieve >99% CD4+ T cells, demonstrated as
naive on the basis of bright L-selectin staining (29). Staining with
mAb did not alter the function of the T cells (not shown).
Dendritic cells were enriched from either BALB/c or C57BL/6 spleen cell preparations, as described previously (17, 30), by first removing adherent cells by overnight culture in plastic flasks followed by overlayering onto 2-ml metrizamide gradients (analytical grade; 13.7%; Nycomed Pharma AS, Oslo, Norway) and centrifugation for 10 min at 600 x g to give a population enriched for dendritic cells in the low density fraction. Dendritic cells (N418highMac-1low) were further purified to homogeneity by flow cytometry as previously described (17).
Stimulation of transgenic CD4+ T cells for cytokine production
Primary stimulations of CD4+ T cells (2.5
x 105/well) were conducted using OVA (0.6 µM) or HEL (1
µM) and dendritic cells (1 x 104/well; 1500 rad) or
RBC-lysed spleen cells (5 x 106/well; 3000 rad) as
APC in a total volume of 2 ml in 24-well plates (Costar). In some
cases, T cells were stimulated with cross-linked anti-CD3
(10
µg/ml) plus IL-2 (10 ng/ml). In addition, some cultures received
cytokines (IL-4 (10 ng/ml) or IL-12 (10 ng/ml)) or mAbs to block
endogenous cytokines (anti-IL-4 (10 µg/ml), anti-IFN- (10
µg/ml), anti-IL-12 (10 µg/ml)). Some cultures also received
TNF- (100 U/ml), IL-1 (10 ng/ml), individually or together with
IL-12 (10 ng/ml). T cells were expanded threefold into fresh medium at
72 h, or 96 h for anti-CD3-stimulated cultures. Cells were
harvested on day 7, washed three times, counted, and restimulated with
fresh APC (splenocytes or dendritic cells) and 0.6 µM OVA or HEL at 1
µM. Cultures previously stimulated with anti-CD3 plus IL-2 were
restimulated with anti-CD3 plus IL-2. The cell concentrations used
were the same as those described for priming. Some cultures also
received TNF- (100 U/ml), IL-1 (10 ng/ml), or IL-12 (10 ng/ml),
either separately or in combination, during the restimulation.
Supernatants were collected at 48 h for the measurement of IL-4
and IFN-. In some cases [3H]thymidine was added to the
cultures for the last 4 h of the 72-h incubation to measure DNA
synthesis.
Committed Th1 cells and Th1 clones
Committed Th1 cells were derived from FACS-sorted naive TCR
transgenic CD4+ T cells as previously described (31).
In brief, cells were cultured with Ag (OVA), and in this case with
dendritic cells in the presence of IL-12 (10 ng/ml) with or without
IL-1 and TNF- to induce Th1 development. Cells were harvested at
7 days and restimulated with fresh dendritic cells and Ag in the
presence of the above cytokines; this process was repeated two
additional times. Committed Th1 populations were restimulated with Ag
(OVA, 0.6 µM) and splenic APC. Supernatants were collected at 48
h and assayed for IFN- and IL-4. Proliferation was assessed by
addition of 1 µCi of [3H]thymidine/well for
6 h.
The Th1 clone HDK1 is a keyhoe limpet hemocyanin-specific clone in the context of I-Ad (32). The Th1 clone was used in experiments at least 10 days after the last Ag stimulation, after culture in medium with IL-2 alone. Th1 clones were stimulated for 48 h in 96-well plates (at 2 x 104/well) either with cross-linked anti-CD3 (10 µg/ml) with or without IL-2 (10 ng/ml) and anti-CD28 (10 µg/ml), or with PMA and ionomycin (50 and 500 ng/ml, respectively). In addition, Th1 clones were stimulated with Ag (keyhole limpet hemocyanin, 500 µg/ml) and dendritic cells for 48 h. Cytokine production was assessed in supernatants at 48 h, and proliferation was assessed by [3H]thymidine incorporation.
Cytokine assays
IFN- was detected using a two-site sandwich ELISA (33). The
sensitivity was 125 pg/ml (1 U/ml = 0.1 ng/ml). The ELISA for IL-4
has been described previously (23), with a level of detectability of
150 pg/ml. Cytokine-secreting cells were assayed on a single cell basis
by flow cytometric analysis of intracellular IFN- and IL-4 synthesis
as previously described (31).
Statistical analysis
Data from multiple experiments were analyzed by comparison to a defined control value using Dunnett’s test. Analysis was performed using JMP software (SAS Institute, Inc., Cary, NC). In defined cases, pairwise comparison was by Student’s paired t test. p < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have previously shown that addition of IL-12 to primary
Ag-driven OVA-specific ß-TCR transgenic CD4+ T
cells stimulated with dendritic cells or spleen cells as APC results in
a Th1 phenotype producing high levels of IFN- upon restimulation
with splenic APC and OVA (8, 17, 18). We now show that IL-12-driven Th1
development of CD4+ T cells primed and restimulated with
dendritic cells as APC gave rise to Th1 cells, but these cells produced
10- to 40-fold less IFN- than T cells primed and restimulated using
spleen cells as APC (Fig. 1
, A
and B). However, dendritic cells were 2 logs more
potent on a per cell basis in inducing the proliferation of
CD4+ T cells both in the primary stimulation (data not
shown) (17) and during the restimulation (Fig. 1, C and
D). This suggested that spleen cells were providing
other cofactors required for IL-12-driven Th1 phenotype
development.
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and TNF- potentiate IL-12-driven Th1 development from
naive DO11.10 ß-TCR transgenic CD4+ T cells
Based on the apparent similarities between costimulators of
IFN- production by T cells and NK cells (8, 11, 17, 34, 35, 36),
possible costimulators for IFN- production by developing Th1 cells
were TNF- and IL-1. To test this, IL-1 and TNF- were first
added to primary cultures of naive CD4+ T cells
stimulated with dendritic cells as APC, either alone or in the presence
of IL-12. Addition of IL-1 or TNF- (either together or
individually) in the absence of IL-12 to primary CD4+ T
cells stimulated with dendritic cells had no effect on the IFN-
levels obtained upon restimulation with spleen APC (Fig. 2A). Addition of
IL-1 to IL-12, in contrast to TNF-, caused a small, but
reproducible, increase in the level of IFN- induced when naive
CD4+ T cells were stimulated with dendritic cells in
primary cultures, but this was still reduced compared with the amounts
of IFN- induced using splenic APC. Although TNF- on its own had
no effect on IL-12-induced Th1 development, a combination of IL-1
and TNF- with IL-12, in primary cultures stimulated with DC, induced
maximal levels of IFN- production equivalent to those induced
following primary stimulation of CD4+ T cells with splenic
APC and Ag (Fig. 2A). The IL-12-induced Th1
development observed in the presence of IL-1 and TNF- was
inhibited significantly by addition of anti-IFN- Abs (Fig. 2B). Furthermore, addition of anti-IL-1,
anti-IL-1R, and anti-TNF- mAbs to cultures of
CD4+ T cells undergoing IL-12-driven Th1 development with
Ag presented by splenic APC significantly reduced IFN- secretion by
these Th1 cells to the level obtained when IL-12-driven Th1 development
was in the presence of dendritic cells as APC (Fig. 3, top).
Isotype-matched control mAbs had no influence on IFN- secretion
(data not shown). In contrast to their effects on IFN- production,
these anti-cytokine Abs did not inhibit T cell proliferation (data
not shown), suggesting a specific requirement for these costimulators
in the induction of IFN-. Although dendritic cells were 100-fold
more potent than splenic APC for induction of proliferation of Th1
cells (Fig. 1
), demonstrating competence as APC for T cell
proliferation, the cofactors required for maximal IFN- production
were clearly provided by splenocytes and not dendritic cells.
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and TNF- are required for maximal IL-12-induced Th1
development in mice on a BALB/c but not C57BL/6 genetic background
Since Th1 development has been shown to be impaired in mice on a
BALB/c background (37, 38, 39, 40), it was important to determine whether this
requirement for IL-1 and TNF- was a general requirement for
IL-12-driven Th1 differentiation or was restricted to this genetic
background. Figure 3 (bottom) clearly shows
that TCR7 mice (C57BL/6), which express an ß-TCR transgene
specific for HEL74–88, show no requirement for IL-1 or
TNF- in IL-12-driven Th1 development when Ag was presented in the
primary cultures on dendritic cells. Furthermore, IL-12-driven Th1
development on spleen APC was not affected by the addition of Abs
directed against IL-1, IL-1 type 1-R, and TNF- (Fig. 3, bottom) in the TCR7 (C57BL/6) mice.
These results suggested that mice on a BALB/c background may not
acquire, or conversely may lose, responsiveness to IL-12 during Th1
development (40). To address this, IL-12 induction of CD25, the IL-2R
subunit, was measured. IL-12 has been previously shown to
up-regulate IL-2 induction of CD25 in Th1 clones (41). IL-12 induced
maximal expression of the CD25 on developing Th1 cells in C57BL/6 mice
stimulated with dendritic cells and Ag, and IL-1 and TNF- did not
increase receptor expression (Fig. 4,
bottom). In contrast, CD4+ T cells from
the DO11.10 mouse, on a BALB/c genetic background, stimulated with
dendritic cells and Ag in the presence of IL-12 showed no increased
level of CD25 expression above the medium control value unless IL-1
and TNF- were also added (Fig. 4, top). IL-1
and TNF- showed no effect on CD25 expression in the absence of IL-12
(data not shown).
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and TNF- in IL-12-driven Th1 development in
CD4+ T cells from DO11.10, BALB/c mice was to counteract
the IL-4 inhibition of IL-12 responsiveness. As shown in Figure 5, although addition of Abs directed
against IL-4 enhanced IL-12-driven Th1 development, the Th1 cells
produced half the levels of IFN- upon restimulation compared with
Th1 cells driven by IL-12 in the presence of IL-1 and TNF-.
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and TNF- potentiate IL-12-driven Th1 development in
BALB/c but not C57BL/6 mice stimulated in an APC-free system
Our data strongly suggested a requirement for IL-1 and TNF-
in IL-12-driven Th1 development in BALB/c but not C57BL/6 mice.
However, these TCR-transgenic mice express different TCR transgenes,
each specific for a different peptide Ag, OVA323–339
and HEL74–88, respectively. Since the affinity of Ag-MHC
for the TCR has been proposed to play a role in determining Th subset
development (14), this may influence this differential responsiveness
to Ag presented on dendritic cells. To rule this out, IL-12-driven Th1
development was examined when CD4+ T cells from BALB/c or
C57BL/6 mice were stimulated in an APC/Ag-free system with cross-linked
anti-CD3 Abs plus IL-2. As shown in Figure 6, IL-12-driven Th1 development was still
reduced in CD4+ T cells obtained from BALB/c compared with
C57BL/6 mice. Furthermore, IL-1 and TNF- potentiated IL-12-driven
Th1 development in BALB/c but not C57BL/6 mice. These data also support
a direct effect of these cofactors on the T cell as well as possible
enhancing effects on APC in previous systems. It is possible that
IL-1 and TNF- increase the amounts of IFN- secreted on a per
cell basis by Th1 cells induced by IL-12, or that these factors
increase the number of IFN--secreting cells within the population.
Flow cytometric analysis of intracellular synthesis of IFN-
demonstrated that these cofactors indeed increased the number of
IFN--secreting Th1 cells resulting from cultures induced with
IL-12.
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and TNF- are cofactors for Th1 development but do not
completely account for maximal IL-12-driven Th1 development observed
when priming and restimulation are induced by spleen APC
IL-12-driven Th1 development observed when CD4+ T
cells were stimulated with anti-CD3 plus IL-2 during primary and
secondary stimulation yielded consistently and significantly lower
levels of IFN- upon restimulation than those observed with splenic
APC, even in the presence of IL-1 and TNF- (Fig. 6). To address
this in more detail, Th1 cells driven by IL-12 plus IL-1 and TNF-
were stimulated in the primary cultures with either dendritic cells or
spleen cells and were then restimulated with DC or spleen cells in the
presence of IL-12 with or without IL-1 and TNF- in an attempt to
restore the levels of IFN- to those seen upon restimulation with
spleen APC. As observed in Figure 7,
although the levels of IFN- seen upon primary and secondary
stimulation with DC in the presence of IL-12, plus IL-1 and TNF-,
were much enhanced by addition of all three factors upon secondary
stimulation with DC, the levels of IFN- achieved were still not
equivalent to those achieved upon restimulation with splenic APC plus
IL-12.
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and TNF-
To determine whether differentiated Th1 cells retain their
responsiveness to the cofactors IL-1 and TNF-, two approaches
were taken. The first was to repeatedly stimulate CD4+
T cells from DO11.10 mice with OVA323–339 and DC in the
presence of IL-12 alone or with IL-12 together with IL-1 and
TNF-. As shown in Figure 8, repeated
restimulation of the Th1 cells showed that there was no difference in
the levels of IFN- produced if they had been stimulated in the
presence or the absence of the cofactors, IL-1 and TNF-. This
could suggest that inhibitors present early during IL-12-induced
development of Th1 cells were lost upon repeated stimulation with the
polarizing stimulus. Additionally, it is possible that committed Th1
cells lose responsiveness to these cofactors. This possibility is
confirmed by a lack of enhancement of IFN- production or
proliferation by Th1 clones by IL-1 and/or TNF- over that seen
with IL-12 alone (Fig. 9), in contrast to
IL-1 mediated increased proliferation of Th2 clones (data not
shown), consistent with prior observations (43).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and TNF- are cofactors
important in IL-12-driven Th1 development in BALB/c but not C57BL/6
mice. This is shown in APC-driven Ag-specific TCR-transgenic T cells
and also in an APC-free system using anti-CD3, confirming a direct
effect on the T cell. Previous studies suggest that APC-derived IL-1 plays an important role as a costimulatory signal for Th2 cells (43, 48). Exogenously supplied IL-1 was shown to costimulate responses of Th2 cells stimulated with mitogens, anti-TCR Abs, or fixed Ag-pulsed APC (43, 46, 48, 49, 50, 51). Furthermore, IL-1 renders Th2 cells sensitive to proliferation induced by IL-4. Some APC, such as monocytes, produce high levels of IL-1 (52) although very potent APC, such as dendritic cells, reportedly do not produce IL-1 (53). Other studies have indicated that certain Th2 clones can produce IL-1 (54, 55) through engagement of CD28 (49), and this leads to increased Th2 IL-4 responsiveness for stimulation of proliferation. In contrast to Th2 cells, there is no evidence to indicate that Th1 cells either produce IL-1 or respond to it (43, 46). In fact, Th1 cells reportedly lack cell surface receptors for IL-1 (43, 48).
Although, Th2 cells clearly respond to IL-1, and Th1 cells lack
responsiveness to this factor, we wished to address its possible role
as a cofactor in Th1 cell development. Evidence that cofactors are
required for IL-12-driven Th1 development is provided in this study. We
show that IL-12-driven Th1 development on dendritic cells or
anti-CD3 yielded low levels of IFN- from Th1 cells upon
restimulation, in contrast to Th1 cells restimulated on spleen APC.
Likely candidates as cofactors included IL-1 and TNF-, since the
production of IFN- by NK cells stimulated with IL-2 or IL-12 has
been shown to be enhanced by IL-1 or TNF- (56, 57, 58), and NK cells
have stimulatory requirements similar to those of Th1 cells (8, 34).
Furthermore, TNF- has been reported to be an adjuvant for Th1
responses (59) and also to synergize with IL-1 for certain biologic
responses (60). Thus, our study lends further evidence for the
similarity of developing Th1 cells and NK cells for the production of
IFN-.
Szabo et al. (42) and Rogge et al. (61) have recently clarified the
molecular basis of the IL-12 unresponsiveness of Th2 cells by showing
the down-regulation of IL-12Rß2 by IL-4. They have further
demonstrated the requirement for IFN- in Th1 development, which to
date has been controversial (9, 10, 17, 18, 42, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71). In addition,
IFN- up-regulates IL-12Rß2 and counteracts the inhibitory effects
of IL-4. Thus, BALB/c mice, which produce a substantial amount of IL-4
(39, 40), may inhibit IL-12Rß2 expression, imposing the reported
requirement for IFN- (42). This may not occur in genetic backgrounds
of mice producing low levels of IL-4, such as B10 and C57BL/6. In the
present study it is likely that IL-1 and TNF- act either to
down-regulate IL-4 or up-regulate IFN- directly, thus increasing the
IL-12 responsiveness of BALB/c T cells. Supporting this conclusion, we
also noted that anti-IL-4 Abs partially counteracted the
requirement for IL-1 and TNF-, but our observation that this was
not complete suggests that other inhibitors may also operate to affect
IL-12 responsiveness. IL-12-driven Th1 development in the BALB/c mouse
in the presence of IL-1 and TNF- is in part dependent on IFN-,
because anti-IFN- reduced this cofactor-dependent Th1
development. Thus, it is likely that these cofactors operate by
increasing levels of IFN- production from developing Th1 cells,
which, as demonstrated by Szabo et al. (42), directly up-regulates the
IL-12Rß-2. Since anti-IFN- did not completely reverse the
effects of IL-1 and TNF-, it is clear that there is an additional
direct effect of these cofactors to increase IL-12 responsiveness.
The results shown in this study may be relevant for understanding
responses to intracellular pathogens. For example, susceptibility or
resistance to Leishmania major in various strains
of mice is complex and probably controlled by several genetic loci (72, 73). Although it is likely to result from the level of IL-12Rß2
expression regulated by IL-4 or IFN-, the immune response may also
be affected by other cofactors, such as IL-1 and TNF- and by
their interplay with T cells and NK cells (36, 56, 58, 74).
Finally, to address the differential stimulation of Th1 vs Th2 cells by
IL-1 published in previous studies, our findings on committed
polarized Th1 cells from TCR-transgenic mice and Th1 clones agree with
the loss of responsiveness of Th1 clones to IL-1 (43) reported
previously.
In summary, we show that IL-1 and TNF- are required for maximal
IL-12-driven Th1 development in BALB/c but not C57BL/6 mice, with
IL-1 having a dominant effect. Although required for potentiation of
IL-12-driven Th1 development in BALB/c mice, these cofactors show no
effect on differentiated Th1 cells.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Anne O’Garra, Department of Immunobiology, DNAX Research Institute of Molecular and Cellular Biology, Inc., 901 California Ave., Palo Alto, CA 94304-1104.
3 Abbreviations used in this paper: HEL, hen egg lysozyme.
Received for publication August 8, 1997. Accepted for publication October 29, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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that drives differentiation of CD4+ T cell subsets and induces early resistance to Leishmania major in mice. J. Exp. Med. 178:567.This article has been cited by other articles:
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  F. Boldizsar, O. Tarjanyi, P. Nemeth, K. Mikecz, and T. T. Glant Th1/Th17 polarization and acquisition of an arthritogenic phenotype in arthritis-susceptible BALB/c, but not in MHC-matched, arthritis-resistant DBA/2 mice Int. Immunol., May 1, 2009; 21(5): 511 - 522. [Abstract] [Full Text] [PDF]
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 S. Lopez Kostka, S. Dinges, K. Griewank, Y. Iwakura, M. C. Udey, and E. von Stebut IL-17 Promotes Progression of Cutaneous Leishmaniasis in Susceptible Mice J. Immunol., March 1, 2009; 182(5): 3039 - 3046. [Abstract] [Full Text] [PDF]
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 H. M. Rowe, L. Lopes, N. Brown, S. Efklidou, T. Smallie, S. Karrar, P. M. Kaye, and M. K. Collins Expression of vFLIP in a Lentiviral Vaccine Vector Activates NF-{kappa}B, Matures Dendritic Cells, and Increases CD8+ T-Cell Responses J. Virol., February 15, 2009; 83(4): 1555 - 1562. [Abstract] [Full Text] [PDF]
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 D. A. Rao, R. E. Eid, L. Qin, T. Yi, N. C. Kirkiles-Smith, G. Tellides, and J. S. Pober Interleukin (IL)-1 promotes allogeneic T cell intimal infiltration and IL-17 production in a model of human artery rejection J. Exp. Med., December 22, 2008; 205(13): 3145 - 3158. [Abstract] [Full Text] [PDF]
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J. Chaix, M. S. Tessmer, K. Hoebe, N. Fuseri, B. Ryffel, M. Dalod, L. Alexopoulou, B. Beutler, L. Brossay, E. Vivier, et al. Cutting Edge: Priming of NK Cells by IL-18 J. Immunol., August 1, 2008; 181(3): 1627 - 1631. [Abstract] [Full Text] [PDF]
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 K. J. Welsh, A. N. Abbott, S.-A. Hwang, J. Indrigo, L. Y. Armitige, M. R. Blackburn, R. L. Hunter, and J. K. Actor A role for tumour necrosis factor-{alpha}, complement C5 and interleukin-6 in the initiation and development of the mycobacterial cord factor trehalose 6,6'-dimycolate induced granulomatous response Microbiology, June 1, 2008; 154(6): 1813 - 1824. [Abstract] [Full Text] [PDF]
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K. Suzue, S. Kobayashi, T. Takeuchi, M. Suzuki, and S. Koyasu Critical role of dendritic cells in determining the Th1/Th2 balance upon Leishmania major infection Int. Immunol., March 1, 2008; 20(3): 337 - 343. [Abstract] [Full Text] [PDF]
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 L. H. Ho, T. Ohno, K. Oboki, N. Kajiwara, H. Suto, M. Iikura, Y. Okayama, S. Akira, H. Saito, S. J. Galli, et al. IL-33 induces IL-13 production by mouse mast cells independently of IgE-Fc{epsilon}RI signals J. Leukoc. Biol., December 1, 2007; 82(6): 1481 - 1490. [Abstract] [Full Text] [PDF]
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 E. Torrado, S. Adusumilli, A. G. Fraga, P. L. C. Small, A. G. Castro, and J. Pedrosa Mycolactone-Mediated Inhibition of Tumor Necrosis Factor Production by Macrophages Infected with Mycobacterium ulcerans Has Implications for the Control of Infection Infect. Immun., August 1, 2007; 75(8): 3979 - 3988. [Abstract] [Full Text] [PDF]
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A. P. Nigg, S. Zahn, D. Ruckerl, C. Holscher, T. Yoshimoto, J. M. Ehrchen, F. Wolbing, M. C. Udey, and E. von Stebut Dendritic Cell-Derived IL-12p40 Homodimer Contributes to Susceptibility in Cutaneous Leishmaniasis in BALB/c Mice J. Immunol., June 1, 2007; 178(11): 7251 - 7258. [Abstract] [Full Text] [PDF]
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S. Nakae, Y. Iwakura, H. Suto, and S. J. Galli Phenotypic differences between Th1 and Th17 cells and negative regulation of Th1 cell differentiation by IL-17 J. Leukoc. Biol., May 1, 2007; 81(5): 1258 - 1268. [Abstract] [Full Text] [PDF]
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 M. Bros, F. Jahrling, A. Renzing, N. Wiechmann, N.-A. Dang, A. Sutter, R. Ross, J. Knop, S. Sudowe, and A. B. Reske-Kunz A newly established murine immature dendritic cell line can be differentiated into a mature state, but exerts tolerogenic function upon maturation in the presence of glucocorticoid Blood, May 1, 2007; 109(9): 3820 - 3829. [Abstract] [Full Text] [PDF]
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 L. D. Hazlett, S. A. McClellan, R. P. Barrett, J. Liu, Y. Zhang, and S. Lighvani Spantide I Decreases Type I Cytokines, Enhances IL-10, and Reduces Corneal Perforation in Susceptible Mice after Pseudomonas aeruginosa Infection Invest. Ophthalmol. Vis. Sci., February 1, 2007; 48(2): 797 - 807. [Abstract] [Full Text] [PDF]
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Q. Chen, G. Sen, and C. M. Snapper Endogenous IL-1R1 Signaling Is Critical for Cognate CD4+ T Cell Help for Induction of In Vivo Type 1 and Type 2 Antipolysaccharide and Antiprotein Ig Isotype Responses to Intact Streptococcus pneumoniae, but Not to a Soluble Pneumococcal Conjugate Vaccine J. Immunol., November 1, 2006; 177(9): 6044 - 6051. [Abstract] [Full Text] [PDF]
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A. Nambu, S. Nakae, and Y. Iwakura IL-1{beta}, but not IL-1{alpha}, is required for antigen-specific T cell activation and the induction of local inflammation in the delayed-type hypersensitivity responses Int. Immunol., May 1, 2006; 18(5): 701 - 712. [Abstract] [Full Text] [PDF]
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J. N. Lozier, N. Tayebi, and P. Zhang Mapping of genes that control the antibody response to human factor IX in mice Blood, February 1, 2005; 105(3): 1029 - 1035. [Abstract] [Full Text] [PDF]
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T. Ebensen, S. Paukner, C. Link, P. Kudela, C. de Domenico, W. Lubitz, and C. A. Guzman Bacterial Ghosts Are an Efficient Delivery System for DNA Vaccines J. Immunol., June 1, 2004; 172(11): 6858 - 6865. [Abstract] [Full Text] [PDF]
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 J. R. Timoshanko, A. R. Kitching, Y. Iwakura, S. R. Holdsworth, and P. G. Tipping Contributions of IL-1{beta} and IL-1{alpha} to Crescentic Glomerulonephritis in Mice J. Am. Soc. Nephrol., April 1, 2004; 15(4): 910 - 918. [Abstract] [Full Text] [PDF]
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A. Iwasaki The Importance of CD11b+ Dendritic Cells in CD4+ T Cell Activation In Vivo: With Help from Interleukin 1 J. Exp. Med., July 21, 2003; 198(2): 185 - 190. [Full Text] [PDF]
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M. Schroder, C. Meisel, K. Buhl, N. Profanter, N. Sievert, H.-D. Volk, and G. Grutz Different Modes of IL-10 and TGF-{beta} to Inhibit Cytokine-Dependent IFN-{gamma} Production: Consequences for Reversal of Lipopolysaccharide Desensitization J. Immunol., May 15, 2003; 170(10): 5260 - 5267. [Abstract] [Full Text] [PDF]
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S. Nakae, Y. Komiyama, H. Yokoyama, A. Nambu, M. Umeda, M. Iwase, I. Homma, K. Sudo, R. Horai, M. Asano, et al. IL-1 is required for allergen-specific Th2 cell activation and the development of airway hypersensitivity response Int. Immunol., April 1, 2003; 15(4): 483 - 490. [Abstract] [Full Text] [PDF]
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C. Deng, C. Radu, A. Diab, M. F. Tsen, R. Hussain, J. S. Cowdery, M. K. Racke, and J. A. Thomas IL-1 Receptor-Associated Kinase 1 Regulates Susceptibility to Organ-Specific Autoimmunity J. Immunol., March 15, 2003; 170(6): 2833 - 2842. [Abstract] [Full Text] [PDF]
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A. C. Herring, J. Lee, R. A. McDonald, G. B. Toews, and G. B. Huffnagle Induction of Interleukin-12 and Gamma Interferon Requires Tumor Necrosis Factor Alpha for Protective T1-Cell-Mediated Immunity to Pulmonary Cryptococcus neoformans Infection Infect. Immun., June 1, 2002; 70(6): 2959 - 2964. [Abstract] [Full Text] [PDF]
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X. Huang, S. A. McClellan, R. P. Barrett, and L. D. Hazlett IL-18 Contributes to Host Resistance Against Infection with Pseudomonas aeruginosa Through Induction of IFN-{gamma} Production J. Immunol., June 1, 2002; 168(11): 5756 - 5763. [Abstract] [Full Text] [PDF]
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B. Wang, C. Feliciani, B. G. Howell, I. Freed, Q. Cai, H. Watanabe, and D. N. Sauder Contribution of Langerhans Cell-Derived IL-18 to Contact Hypersensitivity J. Immunol., April 1, 2002; 168(7): 3303 - 3308. [Abstract] [Full Text] [PDF]
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 C. Du, Q. Guan, M. W. Khalil, and S. Sriram Stimulation of Th2 Response by High Doses of Dehydroepiandrosterone in KLH-Primed Splenocytes Experimental Biology and Medicine, December 1, 2001; 226(11): 1051 - 1060. [Abstract] [Full Text] [PDF]
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J. D. Ahlers, I. M. Belyakov, S. Matsui, and J. A. Berzofsky Signals delivered through TCR instruct IL-12 receptor (IL-12R) expression: IL-12 and tumor necrosis factor-{alpha} synergize for IL-12R expression at low antigen dose Int. Immunol., November 1, 2001; 13(11): 1433 - 1442. [Abstract] [Full Text] [PDF]
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M. Neighbors, X. Xu, F. J. Barrat, S. R. Ruuls, T. Churakova, R. Debets, J. F. Bazan, R. A. Kastelein, J. S. Abrams, and A. O'Garra A Critical Role for Interleukin 18 in Primary and Memory Effector Responses to Listeria monocytogenes that Extends Beyond its Effects on Interferon {gamma} Production J. Exp. Med., August 6, 2001; 194(3): 343 - 354. [Abstract] [Full Text] [PDF]
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D. Stober, R. Schirmbeck, and J. Reimann IL-12/IL-18-Dependent IFN-{{gamma}} Release by Murine Dendritic Cells J. Immunol., July 15, 2001; 167(2): 957 - 965. [Abstract] [Full Text] [PDF]
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J. D. Ahlers, I. M. Belyakov, S. Matsui, and J. A. Berzofsky Mechanisms of cytokine synergy essential for vaccine protection against viral challenge Int. Immunol., July 1, 2001; 13(7): 897 - 908. [Abstract] [Full Text] [PDF]
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S. L. Blass, E. Pure, and C. A. Hunter A Role for CD44 in the Production of IFN-{{gamma}} and Immunopathology During Infection with Toxoplasma gondii J. Immunol., May 1, 2001; 166(9): 5726 - 5732. [Abstract] [Full Text] [PDF]
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A. P. Mountford, K. G. Hogg, P. S. Coulson, and F. Brombacher Signaling via Interleukin-4 Receptor {alpha} Chain Is Required for Successful Vaccination against Schistosomiasis in BALB/c Mice Infect. Immun., January 1, 2001; 69(1): 228 - 236. [Abstract] [Full Text] [PDF]
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V. A. Lawless, S. Zhang, O. N. Ozes, H. A. Bruns, I. Oldham, T. Hoey, M. J. Grusby, and M. H. Kaplan Stat4 Regulates Multiple Components of IFN-{gamma}-Inducing Signaling Pathways J. Immunol., December 15, 2000; 165(12): 6803 - 6808. [Abstract] [Full Text] [PDF]
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J. Wakeham, J. Wang, and Z. Xing Genetically Determined Disparate Innate and Adaptive Cell-Mediated Immune Responses to Pulmonary Mycobacterium bovis BCG Infection in C57BL/6 and BALB/c Mice Infect. Immun., December 1, 2000; 68(12): 6946 - 6953. [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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G. Cai, T. Radzanowski, E. N. Villegas, R. Kastelein, and C. A. Hunter Identification of STAT4-Dependent and Independent Mechanisms of Resistance to Toxoplasma gondii J. Immunol., September 1, 2000; 165(5): 2619 - 2627. [Abstract] [Full Text] [PDF]
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 L. H. Glimcher and K. M. Murphy Lineage commitment in the immune system: the T helper lymphocyte grows up Genes & Dev., July 15, 2000; 14(14): 1693 - 1711. [Full Text]
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M. Kubo, M. Yamashita, R. Abe, T. Tada, K. Okumura, J. T. Ransom, and T. Nakayama CD28 Costimulation Accelerates IL-4 Receptor Sensitivity and IL-4-Mediated Th2 Differentiation J. Immunol., September 1, 1999; 163(5): 2432 - 2442. [Abstract] [Full Text] [PDF]
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Y. Ohshima, L-P. Yang, M-N. Avice, M. Kurimoto, T. Nakajima, M. Sergerie, C. E. Demeure, M. Sarfati, and G. Delespesse Naive Human CD4+ T Cells Are a Major Source of Lymphotoxin {alpha} J. Immunol., April 1, 1999; 162(7): 3790 - 3794. [Abstract] [Full Text] [PDF]
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D. G. Alleva, S. B. Kaser, and D. I. Beller Intrinsic Defects in Macrophage IL-12 Production Associated with Immune Dysfunction in the MRL/++ and New Zealand Black/White F1 Lupus-Prone Mice and the Leishmania major-Susceptible BALB/c Strain J. Immunol., December 15, 1998; 161(12): 6878 - 6884. [Abstract] [Full Text] [PDF]
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A. Porgador, H. F. Staats, Y. Itoh, and B. L. Kelsall Intranasal Immunization with Cytotoxic T-Lymphocyte Epitope Peptide and Mucosal Adjuvant Cholera Toxin: Selective Augmentation of Peptide-Presenting Dendritic Cells in Nasal Mucosa-Associated Lymphoid Tissue Infect. Immun., December 1, 1998; 66(12): 5876 - 5881. [Abstract] [Full Text] [PDF]
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S. L. James, A. W. Cheever, P. Caspar, and T. A. Wynn Inducible Nitric Oxide Synthase-Deficient Mice Develop Enhanced Type 1 Cytokine-Associated Cellular and Humoral Immune Responses after Vaccination with Attenuated Schistosoma mansoni Cercariae but Display Partially Reduced Resistance Infect. Immun., August 1, 1998; 66(8): 3510 - 3518. [Abstract] [Full Text] [PDF]
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