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That Plays a Role in Th1 Priming1
Section of Immunobiology and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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in
the case of Th1 cells and IL-4 in the case of Th2 cells). One issue
that remains unresolved is the source of the early IFN- that
synergizes with IL-12 to fully polarize CD4 T cells into Th1 cells. We
have examined this question by injecting mice with anti-CD3 and
examining cells from normal and various MHC-knockout mice. We found
that IFN- is induced rapidly in a small subset of CD8 T cells. This
subset is absent in mice that lack 
2-microglobulin, but
not in KbDb-double-knockout mice, indicating
that these CD8 T cells are dependent on nonclassical MHC class Ib
molecules. The early burst of IFN- polarizes CD4 T cells toward Th1
cells, in part by stimulating the release of IL-12 from APC. We also
use TAP- and CD1-knockout mice to show that such cells are not
CD1-restricted NK T cells, nor are they dependent on TAP-1 transport
for surface expression of the relevant MHC class Ib molecule.
Therefore, they arise on MHC class Ib molecules that do not depend on
TAP-1 transporters. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and play a crucial role in
eliminating intracellular pathogens, and Th2 cells, which produce
mainly IL-4 and are excellent at inducing humoral immune responses
(1, 2, 3, 4, 5). Considerable effort has been made to investigate
the factors that determine this differentiation of Th cells (6, 7). It is now well established from in vitro as well as in vivo
studies that IL-4 has a predominant role in skewing differentiation
toward Th2 effector cells (8, 9, 10, 11, 12). Likewise, IFN- plays
an important role in inhibiting Th2 cell differentiation. Recent
studies suggest that the decision to differentiate into Th1 or Th2
cells is made at or shortly after stimulation of naive CD4 T cells by
Ag-pulsed dendritic cells
(DC)3 (13, 14).
Previous studies revealed that early IL-4 is produced by NK T cells and
thus posed the possibility that these have a priming function in the
differentiation of Th2 effector cells (8, 15, 16). NK T
cells are mainly CD4+CD8-
or CD4-CD8-, and they use
a restricted TCR with an invariant 
-chain coded for by a canonical
V14J281 join along with either V8 (55%), V7 (10–15%), or
V2 (
7%) (16). Upon stimulation with either
anti-CD3- or anti-CD1-transfected fibroblasts, NK T cells
promptly produce IL-4 (15, 17). Development of this
phenotype is known to depend on CD1, a
2-microglobulin
(2m)-associated non-MHC molecule. Thus,
CD1-mutant mice are devoid of NK T cells (18, 19),
although these mice have a normal frequency of Th1 and Th2 cells
(20, 21).
It was reported that CD8 T cells play an important role in the
generation of protective Th1 immunity (22), but the
mechanism of action of these polarizing T cells and the relationship
between CD8 and CD4 T cells are poorly understood. In contrast, IL-12
has been shown to be a potent inducer of Th1 cells (reviewed in Ref.
23) and also helps in IFN- production by activating NK
cells (24). More recently, it has been established that
IL-12-deficient mice cannot produce an effective Th1 response. Some
bacterial products have been shown to induce IL-12 in DC
(25). Thus, IL-12 is indeed important for Th1 development.
However, no report is yet available that establishes how IL-12 helps
CD8 T cells in the process of production of the early IFN- that is
required for the generation of Th1 effector cells.
It has also been reported that IFN- induces Th1 cell development
(26). Upon neutralization of endogenous IFN-, naive CD4
T cells cultured in the presence of exogenous IL-12 produced
drastically reduced IFN- upon re-stimulation (27, 28),
indicating that IFN- is an essential cofactor for the development of
Th1 cells. Previously, it was reported that upon injection of
anti-CD3, there is rapid production of substantial amounts of
IFN- (15), but the source of this was not identified.
It has also been reported that in vitro stimulation of naive CD8 T
cells induces IFN- synthesis and secretion very rapidly
(29). However, there is no definitive report available
regarding the source and role of IFN- in the early priming of CD4 T
cells.
To gain insight into the requirements for Th1 priming and the source of
the early IFN- that helps to polarize Th1 cells, we used several
available MHC gene-knockout mice. Our results suggest that the initial
IFN- is produced by CD8 T cells and indeed is necessary for priming
CD4 T cells to become polarized Th1 cells. IL-12 enhances the IFN-
production by 5- to 10-fold, but it is not necessary for minimal
generation of this cytokine. Furthermore, detectable IL-12 was observed
in anti-CD3-injected mice, but blocking of IFN- by
anti-IFN- Abs reduced this IL-12 production. This indicated that
the initial synthesis of IFN- may be required for the generation of
IL-12, which in turn is essential for priming Th1 effector cells. Thus,
the initial burst of IFN- has an indirect role via IL-12 induction
in APC and may also have direct role in polarizing Ag-primed naive CD4
cells toward becoming Th1 cells. The experiments outlined in this paper
clearly point to MHC class Ib, TAP-independent cells as producing this
early burst of IFN-.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 (B6) and
B6-2m-/- female mice,
6–8 wk of age, were purchased from The Jackson Laboratories (Bar
Harbor, ME). TAP-/- mice, which had been
backcrossed with B6 mice for 12 generations, were a gift from Dr.
K. A. Hogquist (University of Minnesota, Minneapolis, MN).
KbDb-double-knockout mice
were a gift from Dr. H. Ploegh (Harvard University, Boston, MA). These
mice were backcrossed with B6 mice for four generations. B6-MHC class
II-/- mice were initially purchased from
Taconic Farms (Germantown, NY) and maintained in our animal facility.
TAP-/-CD1-/- mice were
generated by an F1 brother and sister mating of
B6-TAP-/- (12 generations backcrossed with B6)
and B6-129-CD1-/- mice.
B6-129-CD1-/- mice were the kind gift of Dr. L.
Van Kaer (Vanderbilt University, Nashville, TN). These mice had been
previously used for the study of early cytokine production
(18).
Media and reagents
In all experiments, Click’s Eagle Hanks’ amino acid
medium with 10% FCS was used. Anti-CD3 (2C11), isotype control hamster
IgG, rat anti-IFN- (XMG1.2), and rat-anti-IFN- (A4-6A2)
were purified from tissue culture supernatants. Recombinant IFN-,
biotin-labeled anti-IFN- (XMG 1.2), PE-labeled anti-IFN-,
PE-labeled anti-CD44 (Pgp-1), PE-labeled anti-CD45RB,
PE-labeled anti-CD69, and FITC-labeled anti-CD62 ligand (CD62L;
lymphocyte endothelial cell adhesion molecule-1) were purchased from BD
PharMingen (San Diego, CA). FITC-labeled anti-CD4 (H129.19),
FITC-labeled anti-CD8 (53-6.7), and PE-labeled anti-CD8
(53-6.7) Abs were purchased from Life Technologies (Gaithersburg, MD).
LPS and o-phenylenediamine hydrochloride tablets were
purchased from Sigma (St. Louis, MO). Con A was purchased from
Pharmacia Biotech (Uppsala, Sweden).
In vivo treatment of mice
Mice were injected i.v. with a single dose of anti-CD3 (5
µl/mouse) or the same amount of control isotype-matched IgG. At
various indicated time points, spleens were removed for either mRNA
and/or cell preparation. In the in vivo CD4 T cell-priming experiment,
mice were either injected with anti-IFN- (25 µg XMG1.2/mouse),
anti-CD3 alone (5 µg/mouse), or the combination of both. In some
experiments, mice were pre-exposed to LPS (5 µg/mouse) or PBS (100
µl) alone by i.v. injection, either for 4 h as an early time
point or 24 h as a late time point. In the IL-12-blocking
experiment, anti-IL-12 (25 µg anti-p40/p70 per mouse) was
injected together with anti-CD3. For the CD8-positive cell
depletion, B6 and CD1-/- mice were i.v.
injected with anti-CD8 (TIB-210; 50 µg/mouse) Abs every 48 h
for a period of 1 wk.
Cell preparation
After injection, spleens were removed at various time points and
single-cell suspensions were made in 5 ml Click’s Eagle Hanks’ amino
acid medium and 10% FCS, and the cell number was adjusted to 1 x
107 cells/ml. Either 1 x
107 cells were used for preparation of mRNA or
1 x 107 cells/ml were cultured in a 24-well
tissue culture plate (Falcon; BD Biosciences, Franklin Lakes, NJ) for
an additional 1 h in a humidified 5% CO2
chamber at 37°C. Supernatants were harvested for IFN- measurement
by ELISA. For the CD4 T cell-priming experiment, after injection of the
desired Abs, the mice were rested for 3 days, and then their spleens
were harvested and white blood cells were separated on a Ficoll-Hypaque
gradient. Cells were washed twice with complete medium and cultured
(3 x 106 cells/well) in a six-well plate
(Falcon; BD Biosciences) for an additional 24 h along with 2
µg/ml Con A.
Fluorescence analysis and cell sorting
At 3 h after injection, spleens were harvested and
single-cell suspensions were prepared in cold medium. A total of
106 cells were stained in 100 µl staining
buffer (PBS, 3% FCS, and 0.05% NaN3) on ice
with the indicated Abs at the recommended dilution for 30 min, washed,
and fixed with 1% paraformaldehyde. Intracellular IFN- staining was
performed using the Cytofix/CytoPerm Plus kit with GolgiPlug (BD
PharMingen) following the manufacturer’s recommended protocol.
Fluorescence analysis was done using a FACScan flow cytometer (BD
Biosciences). For cell-sorting experiments, spleen cells were harvested
from anti-CD3-injected MHC class II-/- mice
and stained with FITC-anti-CD62L and PE-anti-CD8 for 30 min on
ice. Sorting was conducted using a FACStar flow cytometer (BD
Biosciences). The sorting procedure was performed on ice.
Comparative quantitation of IFN- and IL-12 by RT-PCR
A total of 1 x 107 cells from total
spleen or 0.5 x 106 sorted cells were used
for preparation of mRNA. The mRNA was prepared by TRIzol method
according to the manufacturer’s recommended protocol (Life
Technologies). Finally, cDNA was prepared by using SuperScript and
oligo(dT) (Life Technologies) according to the manufacturer’s
recommended protocol in 100 µl, of which 5 µl was used for RT-PCR.
RT-PCR was performed using specific primers for either IFN- (5'-GAA
AGC CTA GAA AGT CTG AAT AAC T-3' and 5'-ATC AGC AGC GAC TCC TTT TCC GCT
T-3'), IL-12p40 (5'CTG GCC AGT ACA CCT GCC AC-3' and 5'-GTG CTT CCA ACG
CCA GTT CA-3') or hypoxanthine phosphoribosyltransferase (5'-GTT
GGA TAC AGG CCA GAC TTT GTT G-3' and 5'-GAG GGT AGG CTG GCC TAT TGG
CT-3') in 50 µl of volume. At the completion of every five cycles,
10-µl samples were withdrawn. The products were loaded on a 1.5%
agarose gel, and electrophoresis was conducted at 120 V for 45 min. The
gel was stained with ethididium bromide and photographed under
UV light. Products from 5 and 10 cycles were not visible. Therefore,
results were shown starting from 15 cycles.
Detection of IFN- by ELISA
IFN- was detected in culture supernatant using an ELISA
method. Briefly, ELISA plates were coated with 6 µg/ml of
anti-IFN- (A4-6A2) in 100 µl/well in a 96-well Nunc
Immunoplate (Nunc, Roskilde, Denmark) for 2 h at 37°C. Plates
were blocked with blocking buffer (PBS and 1% BSA) for an additional
2 h at 37°C. The plates were then washed with washing buffer
five times, and 100 µl of supernatant per well was incubated at 4°C
overnight. The plates were again washed with washing buffer (PBS and
0.02% Tween 20) five times, and a biotinylated second Ab (XMG1.2) at 1
µl/well was added and incubated for 2 h. Finally, the plates
were incubated with streptavidin-HRP for 1 h at 37°C. Detecting
color was developed by o-phenylenediamine hydrochloride in
citrate buffer (0.05 M sodium phosphate and 0.02 M citric acid (pH
5.0)) and hydrogen peroxide (5 µl 30% hydrogen peroxide per 10 ml of
developing buffer). Plates were read at 490 nm by using ELISA reader
(ELX800; Bio-Tek Instruments, Winooski, VT). The
amount of IFN- produced was calculated from the extrapolated curve
of a known standard graph.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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after anti-CD3 injection in vivo
The goal of these studies was to determine what cell or cells
produce IFN- within the first few hours after stimulation. To do
this, B6 mice were injected either with anti-CD3 at 5 µg/mouse
(at this dose, we get maximum IFN- production; data not shown) or
control hamster Ig in 100 µl PBS. At different time points after
injection, spleens were removed and single-cell suspensions made. A
total of 107 cells were used for preparation of
mRNA encoding IFN- by RT-PCR, and 107 cells/ml
were cultured in 24-well plates for an additional hour at 37°C. A
total of 100 µl supernatant was harvested, and the production of
IFN- was determined by ELISA. Spleens removed at 180 min after
anti-CD3 injection produced maximum expression of IFN- at the
protein level (Fig. 1
a) as
well as at the mRNA level, as determined by RT-PCR (Fig. 1b). There was some expression of IFN- mRNA observed as
early as 45 min. At time points later than 3 h, secretion of
IFN- is reduced. In this experiment, hamster Ig was injected as a
control for anti-CD3, and there was no detectable IFN- produced
in response to hamster Ig at any time point. For additional
experiments, we have taken 180 min as a reference time point unless
otherwise mentioned.
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produced at 3 h is made by CD8 T cells
To investigate the source of this early burst of IFN-, we used
several available gene-knockout mice. We injected B6,
KbDb-/-,
2m-/-,
CD1-/-, MHC class
II-/-, TAP-/-, and
TAP-/-CD1-/- mice with
anti-CD3 (5 µg/mouse). After 3 h, spleens were harvested and
treated as previously described. Little or no IFN- was produced by
2m-/- mice, whereas
there was a modest increase in the amount of IFN- in MHC class
II-knockout mice (Fig. 2a).
2m-deficient mice lack MHC class I
(30) and the receptor that recycles IgG, FcRn
(31). Therefore, the inability of early IFN- production
by the 2m-/- mice
could be due to either cells that are MHC class I dependent or to early
production of IFN- that is coupled with FcRn by an unknown
mechanism. It is clear from these results that MHC class II-restricted
CD4 T cells do not play a significant role as the source of
IFN-.
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2m-dependent nonclassical non-MHC class I
molecule found on mouse chromosome 1. The fact that
CD1-/- mice made 50% of the early IFN-
compared with their wild-type littermate suggests that CD1-restricted T
cells are one of the early IFN- source. The source of the remaining
50% of early IFN- is dependent on 2m
but independent of TAP. This observation directed our attention to MHC
class Ib molecules as a possible source of the remainder of the
observed early burst of IFN-.
From in vitro studies, it was shown that, upon activation, NK T cells
are capable of producing both early IL-4 and early IFN-
(17). Thus, we evaluated the production of IFN- in
CD1-knockout mice and noticed there was about a 50% decrease in
IFN- secretion, suggesting that the NK T cell is one of the early
IFN- producers. TAP-/- and
TAP-/-CD1-/- mice also
produce a considerable amount of IFN- (Fig. 2
a). Previous
in vitro studies had shown that upon activation, naive CD8 T cells
produce substantial amounts of IFN- (29). Moreover,
even in mice with a deletion of the TAP-1 protein, there are still a
considerable number of CD8 T cells remaining (32), and
they are MHC class Ib restricted. Therefore, the source of the early
burst of IFN- could be CD8 T cells restricted to one or more MHC
class Ib genes. To test this hypothesis, we performed an experiment
using CD8 T cell-depleted mice. These mice show a 40–50% reduction in
the early burst of IFN- (Fig. 2b). Thus, we conclude that
the early burst of IFN- is produced by both NK T cells and CD8 T
cells, at least some of which are MHC class Ib restricted.
Early IFN- can prime CD4+ T cells to be
IFN--producing effector cells
To evaluate the physiological role of the observed initial burst
of IFN-, we established a system to measure whether this cytokine
plays a role in priming CD4 T cells. To do this, we injected mice
either with anti-CD3 alone, anti-IFN- alone, or a
combination of both Abs and rested the animals for 72 h. It is
known that the decision to differentiate is made early
(14), but CD4 T cell priming and commitment takes at least
72 h (29). Therefore, the spleens were removed 3 days
after Ab injection, and the cells were cultured in the presence of Con
A for 24 h and stained for surface CD4 and for intracellular
IFN-. Mice that were preinjected with anti-CD3 alone produced a
predominant peak of CD4 T cells making IFN-, whereas those injected
with anti-IFN- and anti-CD3 showed very few CD4 T cells
producing IFN- (Fig. 3). Hence, in
vivo, the early production of IFN- is important for priming CD4 T
cells that produce IFN- upon full differentiation.
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-producing cells
We were interested to determine whether the CD8 T cells
responsible for the early burst of IFN- were of a distinct surface
phenotype. To do this, we examined the changes in activation markers on
the cells 3 h after anti-CD3 injection. Fig. 4a depicts a marked change in
the expression of CD62L and CD69, but no significant difference in the
expression pattern of CD44 and CD45. We sorted the
CD8+CD62Lhigh and
CD8+CD62Llow cells after
anti-CD3 injection to look at their IFN- mRNA content. Analysis
of mRNA by RT-PCR with IFN--specific primers (Fig. 4b)
determined that
CD8+CD62Llow cells have
more IFN- mRNA than the
CD8+CD62Lhigh cells,
consistent with the more mature CD62Llow
phenotypes.
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production
In a pathogenic insult, T cells recognize Ag only if it is
displayed by an APC. It is also known that, without activation of APC,
tolerance rather than immunity is the usual result. Only activated APC
have the capability for increased production of Ag-loaded MHC molecules
and the induction of costimulatory molecules. Without simultaneous
recognition of costimulatory molecules along with Ag, the T cells
become anergic. In addition, activated APC (especially macrophages and
DC) produce proinflammatory cytokines such as IL-1 and IL-12. To
enhance immune responses to foreign protein Ags, these need to be
injected in adjuvants. Activation of APC by adjuvant increases
expression of many molecules that interact with naive T cells, such as
peptide-loaded MHC molecules, costimulatory molecules, and T
cell-priming cytokines such as IL-12 and IL-6. APC-derived cytokines
may have some role in the elevation and polarization of T cell
responses. Indeed, IL-12 has been shown to be important for the
development of Th1 cells (7, 23, 24), and IL-6 plays an
important role in polarization of Th2 responses (reviewed in Ref.
6), whereas IL-10 has been shown to repress secretion of
proinflammatory cytokines. Thus, we investigated a possible role of APC
activation in the production of early IFN- by CD8 T cells.
Professional APC have a high number of receptors for abundant
pathogen-associated molecular patterns such as LPS. Upon activation
with LPS, macrophages and DC express high levels of MHC class II and
costimulatory molecules and secrete soluble factors, such as IL-12,
IL-6, and IL-10, that are involved in T cell polarization. In the
present case, because we are providing anti-CD3 in vivo, there is
no obvious involvement of APC activation leading to the secretion of
soluble factors. Hence, we investigated whether activation of APC can
further increase the early secretion of IFN-. To do so, we
pre-exposed mice to LPS and then injected them with anti-CD3. It
was found that 4 h after exposure to LPS, the amount of secreted
IFN- was enhanced by 5- to 10-fold, but by 24 h after exposure
to LPS, the mice produced almost an equal amount of IFN- when
compared with that of unexposed control mice (Fig. 5a). This indicated that
activation of APC indeed enhances the production of early IFN-.
Interfering with the interaction between anti-CD3-bound T cells and
APC by injecting anti-FcR Ab drastically reduced the early IFN-
production (Fig. 5b). Therefore, APC-T cell interaction is
necessary for the production of early IFN-, most likely by blocking
presentation of anti-CD3 with anti-FcR. The inhibition in the
production of early IFN- in anti-FcR-injected mice could be due
to the lack of activation of T cells resulting from the lack of
interaction between T cell and APC. CD8 T cells failed to be activated
in anti-FcR-injected mice (Fig. 5c). Engagement of
FcR has been shown to produce a reduced amount of IL-12
(33) in macrophages. However, it is less likely that IL-12
is required for the activation of early IFN--producing cells,
because injection of anti-IL-12 did not inhibit the minimal
production of IFN- (Fig. 6a).
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secretion but
helps by enhancing its induction
From the preceding results, it is clear that for early IFN-
secretion, there is a requirement of T cell-APC interaction that is
enhanced by LPS activation of the APC. Earlier studies revealed that
IL-12 is important for Th1 development (7, 23), and
indeed, IL-12-deficient mice fail to make Th1 responses. To examine the
role of IL-12 in early IFN- production, we blocked IL-12 with
anti-IL-12 Abs before injection of anti-CD3 in either normal or
LPS-pretreated mice. Surprisingly, the results indicated that there was
no difference in early IFN- secretion between anti-IL-12-treated
and nontreated mice. However, blocking of IL-12 in LPS-pretreated mice
resulted in a marked reduction in IFN- production (Fig. 6a). This observation suggests that IL-12 may be an
enhancing factor for the induction of early IFN- production by CD8 T
cells. Furthermore, we noted that there was detectable IL-12 in
anti-CD3-injected mice, but upon blocking IFN- by injecting
anti-IFN-, IL-12 induction was reduced (Fig. 6b).
Thus, it seems that early secretion of IFN- is independent of
IL-12. However, IL-12 secretion by LPS-induced activation of APC may
enhance the early secretion of IFN- by CD8 T cells. Furthermore,
when the interaction of APC with T cells is inhibited with
anti-FcR, the observed increase in IL-12 mRNA is reduced to levels
similar to those seen after anti-IFN- treatment.
Thus, early IFN- secretion may help the adaptive immune response in
two ways. First, it may activate APC to initiate production of IL-12 as
well as priming CD4 T cells. Second, the IL-12 produced by the APC
further helps CD8 T cells by enhancing IFN- production. By both
mechanisms, IL-12 from APC, together with IFN- from CD8 T cells,
helps to direct the naive CD4 T cells to become effector Th1 cells. It
is possible that, in the natural situation of antigenic challenge,
IL-12 is produced because of two parallel events: first, because of
direct activation of the APC by pathogen or its pathogen-associated
molecular patterns, and second, by IFN- produced by the stimulated
CD8 T cells. Thus, in turn, IL-12 and IFN-, along with IL-2, induce
the clonal expansion of effector Th1 cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-producing
cells is rather complex. A number of studies have emphasized that IL-12
has a predominant role in Th1 priming (23). However, at
the same time, it has also been shown that neutralization of IFN- in
the various culture systems abolishes IFN- production by CD4 T cells
(27, 28), suggesting that there is also a crucial role of
IFN- in the process of Th1 polarization.
Our studies reveal that early IFN- has a role in polarizing CD4 T
cells to become Th1 cells. In a search for the source of this early
IFN-, it seems most likely that a distinct population of CD8 T
cells produces this cytokine. Because these CD8 T cells arise
independently of MHC class Ia molecules, as shown by their presence in
KbDb-/- and B6 mice, it
seems likely that they develop on MHC class Ib molecules, which is
shown by their dependency on 2m.
IL-4 and IFN- are thought to be regulating cytokines rather growth
factors. Thus, the physiological relevance of the early appearance of
such cytokines could be important during the process of polarization of
the CD4 T cell response by providing an appropriate microenvironment.
It is important to note that neither
2m-/- nor
CD1-/- mice show any biased frequency of Th1 or
Th2 cells (18, 19, 20, 21, 37, 38). This suggests that the early
bursts of these regulatory cytokines are able to help in the process of
polarization, but they are not the sole agents.
There are two potential advantages of having a nonclassical MHC class Ib restriction element controlling these regulatory cells. First, the binding of Ags by nonclassical MHC class Ib molecules does not require conventional pathways of Ag presentation, and hence, they are readily accessible for recognition. Second, the Ags that bind to the nonclassical MHC class Ib molecules are abundant, such as the binding of lipids by CD1, the binding of MHC class I leader peptide to Qa-1, and the binding of N-formyl methionine peptides to H2-M3. Thus, the accessibility of Ag for these cells occurs at earlier times than happens with conventional MHC class Ia Ags. Finally, their activity helps in directing the polarization of the final outcome of a T cell response.
The polarization of Th1-mediated immune responses is strengthened by
IL-12. IL-12 is generally produced by professional APC such as
macrophages and DC. Our experiments suggest that IL-12 enhances the
early IFN-, but the initiation of IL-12 expression is dependent on
activation of the APC either directly by Ags, such as LPS, or by the
secretion of IFN- derived from the CD8 T cells.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Charles A. Janeway, Jr., Section of Immunobiology and Howard Hughes Medical Institute, Yale University School of Medicine, P.O. Box 208011, 310 Cedar Street, New Haven, CT 06520-8011. E-mail address: charles.janeway{at}yale.edu
3 Abbreviations used in this paper: DC, dendritic cells; 2m, 2-microglobulin; CD62L, CD62 ligand.
Received for publication September 13, 2000. Accepted for publication June 5, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and is inhibited by transforming growth factor-. Eur. J. Immunol. 24:793.[Medline]
in regulation of Th1 cell development. J. Immunol. 157:1350.[Abstract]
2-microglobulin-deficient mice lack CD4-CD8+ cytolytic T cells. Nature 344:742.[Medline]
2-microglobulin-containing neonatal intestinal transport receptor. Proc. Natl. Acad. Sci. USA 93:5512.2-microglobulin-dependent T cells are dispensable for allergen-induced T helper 2 responses. J. Exp. Med. 184:1507.This article has been cited by other articles:
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 A. Kosaka, D. Wakita, N. Matsubara, Y. Togashi, S.-I. Nishimura, H. Kitamura, and T. Nishimura AsialoGM1+CD8+ central memory-type T cells in unimmunized mice as novel immunomodulator of IFN-{gamma}-dependent type 1 immunity Int. Immunol., March 1, 2007; 19(3): 249 - 256. [Abstract] [Full Text] [PDF]
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P. Pandiyan, J. K. E. Hegel, M. Krueger, D. Quandt, and M. C. Brunner-Weinzierl High IFN-{gamma} Production of Individual CD8 T Lymphocytes Is Controlled by CD152 (CTLA-4) J. Immunol., February 15, 2007; 178(4): 2132 - 2140. [Abstract] [Full Text] [PDF]
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 G. Das, J. Das, P. Eynott, Y. Zhang, A. L.M. Bothwell, L. V. Kaer, and Y. Shi Pivotal roles of CD8+ T cells restricted by MHC class I-like molecules in autoimmune diseases J. Exp. Med., November 27, 2006; 203(12): 2603 - 2611. [Abstract] [Full Text] [PDF]
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S. Dhanji, M. T. Chow, and H.-S. Teh Self-Antigen Maintains the Innate Antibacterial Function of Self-Specific CD8 T Cells In Vivo J. Immunol., July 1, 2006; 177(1): 138 - 146. [Abstract] [Full Text] [PDF]
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N. Mikhalkevich, B. Becknell, M. A. Caligiuri, M. D. Bates, R. Harvey, and W.-p. Zheng Responsiveness of Naive CD4 T Cells to Polarizing Cytokine Determines the Ratio of Th1 and Th2 Cell Differentiation J. Immunol., February 1, 2006; 176(3): 1553 - 1560. [Abstract] [Full Text] [PDF]
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J. Su, R. E. Berg, S. Murray, and J. Forman Thymus-Dependent Memory Phenotype CD8 T Cells in Naive B6.H-2Kb-/-Db-/- Animals Mediate an Antigen-Specific Response against Listeria monocytogenes J. Immunol., November 15, 2005; 175(10): 6450 - 6457. [Abstract] [Full Text] [PDF]
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L. K. Teixeira, B. P. F. Fonseca, A. Vieira-de-Abreu, B. A. Barboza, B. K. Robbs, P. T. Bozza, and J. P. B. Viola IFN-{gamma} Production by CD8+ T Cells Depends on NFAT1 Transcription Factor and Regulates Th Differentiation J. Immunol., November 1, 2005; 175(9): 5931 - 5939. [Abstract] [Full Text] [PDF]
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A. J. Mitchell, A. M. Hansen, L. Hee, H. J. Ball, S. M. Potter, J. C. Walker, and N. H. Hunt Early Cytokine Production Is Associated with Protection from Murine Cerebral Malaria Infect. Immun., September 1, 2005; 73(9): 5645 - 5653. [Abstract] [Full Text] [PDF]
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 M. Feili-Hariri, D. H. Falkner, and P. A. Morel Polarization of naive T cells into Th1 or Th2 by distinct cytokine-driven murine dendritic cell populations: implications for immunotherapy J. Leukoc. Biol., September 1, 2005; 78(3): 656 - 664. [Abstract] [Full Text] [PDF]
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M. M. Freeman and H. K. Ziegler Simultaneous Th1-Type Cytokine Expression Is a Signature of Peritoneal CD4+ Lymphocytes Responding to Infection with Listeria monocytogenes J. Immunol., July 1, 2005; 175(1): 394 - 403. [Abstract] [Full Text] [PDF]
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S. Arce, H. F. Nawar, M. W. Russell, and T. D. Connell Differential Binding of Escherichia coli Enterotoxins LT-IIa and LT-IIb and of Cholera Toxin Elicits Differences in Apoptosis, Proliferation, and Activation of Lymphoid Cells Infect. Immun., May 1, 2005; 73(5): 2718 - 2727. [Abstract] [Full Text] [PDF]
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 M.-E. Blais, G. Gerard, M. M. Martinic, G. Roy-Proulx, R. M. Zinkernagel, and C. Perreault Do thymically and strictly extrathymically developing T cells generate similar immune responses? Blood, April 15, 2004; 103(8): 3102 - 3110. [Abstract] [Full Text] [PDF]
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 K. Klingel, J.-J. Schnorr, M. Sauter, G. Szalay, and R. Kandolf {beta}2-Microglobulin-Associated Regulation of Interferon-{gamma} and Virus-Specific Immunoglobulin G Confer Resistance Against the Development of Chronic Coxsackievirus Myocarditis Am. J. Pathol., May 1, 2003; 162(5): 1709 - 1720. [Abstract] [Full Text] [PDF]
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A. C. Kirby, U. Yrlid, and M. J. Wick The Innate Immune Response Differs in Primary and Secondary Salmonella Infection J. Immunol., October 15, 2002; 169(8): 4450 - 4459. [Abstract] [Full Text] [PDF]
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R. B. Smeltz, J. Chen, R. Ehrhardt, and E. M. Shevach Role of IFN-{gamma} in Th1 Differentiation: IFN-{gamma} Regulates IL-18R{alpha} Expression by Preventing the Negative Effects of IL-4 and by Inducing/Maintaining IL-12 Receptor {beta}2 Expression J. Immunol., June 15, 2002; 168(12): 6165 - 6172. [Abstract] [Full Text] [PDF]
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