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14 NK T Cells1
Departments of
*
Demyelinating Disease and Aging and
Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan; and
CREST Project, Japan Science and Technology Corporation and Department of Molecular Immunology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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14 NK T cells with the
CD1d-restricted ligand -galactosylceramide (-GC). EAE induced in
wild-type C57BL/6 (B6) mice was not appreciably altered by injection of
-GC. However, EAE induced in IL-4 knockout mice and IFN-
knockout
mice was enhanced or suppressed by -GC, respectively. This indicates
that the IL-4 and IFN- triggered by -GC may play an inhibitory or
enhancing role in the regulation of EAE. We next studied whether NK T
cells of wild-type mice may switch their Th0-like phenotype toward Th1
or Th2. Notably, in the presence of blocking B7.2 (CD86) mAb, -GC
stimulation could bias the cytokine profile of NK T cells toward Th2,
whereas presentation of -GC by CD40-activated APC induced a Th1
shift of NK T cells. Furthermore, transfer of the -GC-pulsed APC
preparations suppressed or enhanced EAE according to their ability to
polarize NK T cells toward Th2 or Th1 in vitro. These results have
important implications for understanding the role of NK T cells in
autoimmunity and for designing a therapeutic strategy targeting NK T
cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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V14 NK T cells (12, 13) constitute a unique lymphocyte
population that may serve as a target for immunotherapy. NK T cells are
phenotypically characterized by expression of semi-invariant
V14-J281/V
8 TCRs (V24-JQ/V11 TCRs for human) and NK
cell markers including NKR-P1. Unlike conventional T cells, they
are not MHC restricted but recognize glycolipid Ags such as
-galactosylceramide (-GC) in association with monomorphic CD1d
molecule (14, 15, 16, 17). Because NK T cells can produce large
amounts of IL-4 and IFN- shortly after TCR ligation, it was
initially believed that they serve as a critical source of IL-4 needed
for differentiation of Th2 T cells. It is now clear that the presence
of NK T cells is not an absolute requirement for Th2 T cell priming
(18, 19, 20). However, lines of evidence support its role in
immunoregulation (21, 22, 23). In the present study, we
attempted to treat EAE by stimulating NK T cells with -GC.
-GC was originally isolated as a natural product from marine sponges
(14). Several studies have demonstrated that both mouse
and human NK T cells recognize -GC in the context of CD1d and that
reactivity to -GC is highly specific for NK T cells. NK T cells
activated by -GC would exhibit various biological functions mediated
by an NK-like cytotoxicity (24) or a vigorous production
of IL-4 and IFN- (14, 15, 16, 17). The potential to stimulate
the cytokine production indicates that -GC may be useful for control
of autoimmune diseases by altering the Th1/Th2 balance. However,
opposing theories have been provided regarding the possible effect of
-GC on immune-mediated diseases. Cui et al. (25)
speculated a therapeutic effect of -GC for Th2 cell-mediated
diseases based on its potential to induce IFN- production by NK T
cells, whereas other studies (26, 27) indicate that -GC
induces a Th2 shift of NK T cells and is effective for treatment of
Th1-mediated diseases. However, none of these have examined the effect
of -GC on autoimmune disease models. Of note, in the latter studies
(26, 27), this immunogenic glycolipid was injected
repeatedly (27) or administered in an emulsion mixed with
an adjuvant (26) to sensitize against -GC. It is
possible that the Th2 polarization of NK T cells in vivo may be due to
the sensitization, but the underlying mechanism remains unclear. Here
we administered a single injection of -GC solution without adjuvant
or transferred -GC-pulsed APC preparations after fixation. Using the
single-injection protocols, we analyzed the mechanism of -GC-induced
immunomodulation in vitro and in vivo. Here we demonstrate that NK T
cells displayed differential Th1 or Th2 phenotype on -GC recognition
according to the costimulation signals and that -GC can either
suppress or enhance EAE when NK T cells are polarized to Th2 or Th1,
respectively.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B6 mice were purchased from the CLEA Laboratory Animal Corp.
(Tokyo, Japan). IFN- knockout (KO) mice and IL-4 KO mice with the B6
background were purchased from The Jackson Laboratory (Bar Harbor, ME).
NK T KO mice were established by specific deletion of the J281 gene
segment with homologous recombination and aggregation chimera
techniques (24) and were backcrossed nine times with B6
mice. All of the mice were kept under specific pathogen-free
conditions, and only female mice (6–10 wk of age) were used. Myelin
oligodendrocyte glycoprotein (MOG35–55; amino
acid sequence in single-letter code, MEVGWYRSPFSRVVHLYRNGK) was
synthesized at Chiron Technologies (Clayton, Victoria, Australia). IFA
and heat-killed Mycobacterium tuberculosis H37Ra were
purchased from Difco (Detroit, MI) and pertussis toxin (PT) from Sigma
(St. Louis, MO). Unlabeled or biotin-conjugated anti-mouse IFN-
and anti-IL-4 mAbs and azide-free anti-B7.1 (CD80),
anti-B7.2 (CD86), and anti-CD40 (HM40-3) mAbs were obtained
from PharMingen (San Diego, CA). The anti-B7 Abs block B7-CD28
costimulation, while the anti-CD40 is an agonistic mAb.
Biotin-conjugated anti-IgG1, anti-IgG2a, and anti-IgE were
obtained from Southern Biotechnology Associates (Birmingham, AL).
-GC was synthesized according to a previously described method
(28).
Immunization
Active EAE in wild-type B6 mice was induced as previously
described (7). Briefly, the mice were challenged in the
hind footpads with an emulsion containing 200 µg of
MOG35–55 and 500 µg of M.
tuberculosis in IFA. Booster immunization with an identical
emulsion was given on both sides of the flank 1 wk later. PT (500 ng)
was injected i.v. shortly after and 48 h after the first and
second immunizations. For induction of EAE in IFN- KO and IL-4 KO
mice, the doses for MOG35–55 peptide and PT were
reduced (peptide, 100 µg/mouse; PT, 250 ng/mouse) because the
protocol for wild-type B6 was found to induce illness that was too
serious (our unpublished data).
In vivo injection of -GC or -GC-pulsed spleen APC
-GC was first dissolved in DMSO at 100 µg/ml and then
diluted in PBS. -GC (100 µg/kg in 200 µl) was injected i.p. on
the day of first immunization for active EAE, unless otherwise
indicated. Control groups received 200 µl of PBS. For treatment with
-GC-pulsed APC, the spleen cells from wild-type B6 mice were
x-irradiated (4000 rad) and were incubated with 100 ng/ml of -GC
and/or relevant mAb (10 µg/ml) in PBS for 4 h. The pulsed APCs
were washed and then fixed in 3% paraformaldehyde for 5 min. After
intensive washing in PBS, 1 x 107 cells
were injected i.p. into the mice on day 1 after first immunization with
MOG35–55 for active EAE induction.
Proliferation assay for V14 NK T cells
Total spleen cells were suspended in RPMI 1640 supplemented with
5 x 10-5 M 2-ME, 2 mM
L-glutamine, 100 U/mg/ml penicillin/streptomycin, and 1%
syngeneic mouse serum (standard medium). The cells were cultured with
or without -GC (100 ng/ml) in 96-well flat-bottom plates at 5
x 105/well for 72 h (37°C, 5%
CO2 atmosphere). Incorporation of
[3H]thymidine (1 µCi/well) for the final
16 h of the culture was determined with a -1205 counter
(Pharmacia, Uppsala, Sweden).
Cytokine assay
Total spleen cells were suspended in the standard medium and
were cultured with or without -GC (100 ng/ml) in 96-well U-bottom
plates (5 x 105/well) for 48 h.
IFN- and IL-4 levels in the culture supernatants were measured by a
standard sandwich ELISA, using purified and biotinylated Ab pairs and
standards from PharMingen. IL-12 was measured with a commercial kit
from R&D Systems (Minneapolis, MN).
Measurement of MOG35–55-specific IgG1 and IgG2a
Immunoplates (Maxisorp; Nunc, Rochester, NY) were coated with 10
µg/ml MOG35–55 in phosphate buffer overnight.
After blocking with 1% BSA in PBS, serial dilutions (x10
10,000) of
the serum from sensitized mice or normal mouse or PBS were added onto
MOG35–55-coated wells. For detection of
anti-MOG35–55 Abs, the plates were incubated
with biotin-labeled anti-IgG1, anti-IgG2a, or anti-IgE Ab
for 1 h and then incubated with streptavidin-peroxidase. After
adding a substrate, the reaction was evaluated and Ab titers were
calculated on the basis of dilution/absorbance curves.
Clinical assessment
Mice were observed daily for clinical signs of EAE. The severity of EAE was evaluated and scored as follows: 0 = normal; 1 = weakness of the tail and/or paralysis of the distal half of the tail; 2 = loss of tail tonicity and abnormal gait; 3 = partial hindlimb paralysis; 4 = complete hindlimb paralysis; 5 = forelimb paralysis or moribundity; 6 = death. The cumulative disease score was also calculated for an individual mouse by summing up the daily disease scores. The Mann-Whitney rank-sum test was used for statistical analysis of the clinical scores.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-GC in vivo
Previous studies (14, 15, 16, 17) have demonstrated that
-GC stimulates NK T cells to produce both IL-4 and IFN-. To
ascertain that the amount of -GC (100 µg/kg) is relevant for
activating NK T cells in vivo, we measured the serum cytokine levels at
different time points after injection of -GC. As shown in Fig. 1
, -GC induced a rapid rise of IL-4
with the peak value at 2 h and a delayed elevation of IL-12 (peak
value at 6 h) and IFN- (peak at 12 h) in the serum of
wild-type B6 mice. In contrast, these cytokines were not detected in NK
T KO mice after injection of -GC (IFN-, <0.1 ng/ml; IL-4, <0.02
ng/ml). The elevation of IFN- and IL-4 in -GC-treated mice is
consistent with a previous study (26), and the IL-12
elevation corresponds to the report that -GC induces IL-12
production by dendritic cells (29).
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-GC on actively induced EAE
To clarify the effect of -GC on EAE, we injected this NK T cell
ligand into wild-type B6 mice on the first day of active challenge with
MOG35–55. Although we saw a slight enhancement
of cumulative score in the -GC-treated mice (Fig. 2A; Table I), there was no significant difference
in the day of onset or maximum clinical score between the two groups.
In addition, some mice were injected with -GC shortly before EAE
development (on day 15) or injected repeatedly on days 0, 3, 6, 9, and
12. Neither of the protocols induced a significant change in the
clinical course (not shown). EAE induced in NK T KO mice was also
treated with -GC, but there was no significant difference between
-GC-treated and control groups in the day of onset, mean maximum
score, and duration of illness (data not shown).
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-GC stimulation induces
not only Th2 (IL-4) but also Th1 cytokine (IFN-)
(14, 15, 16, 17). We speculated that the disease-protective effect
of IL-4 from ligand-activated NK T cells might be counteracted by
simultaneously produced IFN-. To verify this postulate, we examined
the effect of -GC on EAE induced in mice of which the NK T cells
were unable to secrete either IL-4 (IL-4 KO mice) or IFN- (IFN-
KO mice). In vitro experiments showed that spleen NK T cells from IL-4
KO or IFN- KO mice produced IFN- or IL-4 in response to -GC,
respectively (Fig. 3). However,
stimulation of NK T KO spleen cells did not induce any of the
responses, indicating that the -GC-induced responses are NK T cell
dependent. As shown in Fig. 2
B and Table I, EAE induced in
IL-4 KO mice was significantly enhanced by -GC treatment in
cumulative disease score. In contrast, EAE induced in IFN- KO mice
was significantly inhibited both in maximum and cumulative scores (Fig. 2C). These results imply that IFN- triggered by -GC
augments EAE, whereas IL-4 protects against EAE.
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-GC stimulation of NK T cells with B7.2 blockade leads to NK T
cell polarization toward Th2 and suppression of EAE
Seeing the remarkable modulation of EAE by -GC in the cytokine
KO mice, we questioned whether or not -GC-stimulated NK T cells from
wild-type mice could be modulated from the Th0 cytokine phenotype
toward either Th1 or Th2. Previous reports demonstrate that the Th1/Th2
phenotype of conventional T cells can be altered by ligand
stimulation without proper B7/CD28 costimulation (32, 33).
To know whether these observations can be extrapolated to NK T cells,
we stimulated spleen NK T cells with -GC in the presence of either
B7.1 (CD80) or B7.2 (CD86) blocking mAb and measured IFN- and IL-4
levels in the supernatants. As shown in Fig. 4, stimulation of B6 spleen cells with
-GC induced production of IFN- and IL-4, as well as cell
proliferation. In the presence of anti-B7.1 mAb, the proliferative
response was mildly enhanced, but production of IFN- or IL-4 was
little affected. We also evaluated the Th1/Th2 phenotype of NK T cells
by calculating the proportion of Th1 (IFN-) to Th2 cytokine (IL-4)
in the supernatant (referred to as IFN-/IL-4 ratio below). There was
no significant difference in the IFN-/IL-4 ratio between the
-GC-stimulated culture (the IFN-/IL-4 ratio; 5.36.0) and the
-GC-stimulated culture with anti-B7.1 mAb (6.16.2). In
contrast, anti-B7.2 mAb inhibited cell proliferation and cytokine
production. In particular, IFN- production was most greatly
inhibited. As a result, the IFN-/IL-4 ratio was remarkably reduced
in the -GC-stimulated culture with anti-B7.2 (1.12.9).
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-GC stimulation
with B7.2 blockade might lead to suppression of EAE by shifting NK T
cells toward Th2. To verify this idea, a simple coinjection of -GC
and anti-B7.2 mAb was avoided because a systemic injection of the
mAb would inhibit immune responses at multiple levels. Instead, we
examined the effect of -GC-pulsed spleen APC of wild-type mice of
which the B7.2 expression was blocked with the anti-B7.2 Ab (Fig. 5, APC+GC+B7.2). Control groups of mice
were transferred with APC alone, APC pulsed with -GC (APC+GC), APC
treated with anti-B7.2 mAb, or -GC-pulsed APC treated with
anti-B7.1 mAb. While all of the mice in the control groups
developed EAE, only half of the mice in the treatment group
(APC+GC+B7.2) developed EAE, and with a shorter duration of
illness (Fig. 5A). As a result, a marked suppression of
cumulative EAE scores was seen in the APC+GC+B7.2 treatment group (Fig. 5B).
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, the
APC+GC+B7.2 treatment did not cause significant suppression of EAE as
compared with the APC or APC+GC treatment. Taking these findings
together, we conclude that the suppression of EAE was mediated by NK T
cells in the wild-type mice treated with APC+GC+B7.2.
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-GC stimulation of NK T cells with CD40-activated APC leads to
Th1 polarization of NK T cells and enhancement of EAE
In an initial screening of mAbs, we noted that IL-4 production
triggered by -GC was severely suppressed in the presence of an
agonistic anti-CD40 mAb, whereas IFN- production was not altered
(Fig. 4). Of note, there was a dramatic increase in the IFN-/IL-4
ratio in the supernatant (100132). To further correlate the Th1/Th2
profile of NK T cells in vitro and their disease-modifying potential in
vivo, we treated mice sensitized for EAE with APC alone, APC treated
with anti-CD40 mAb, or -GC-pulsed APC treated with anti-CD40
mAb (APC+CD40+GC). As shown in Fig. 7, the latter two groups showed a delayed onset of disease as compared
with the APC group. The APC+CD40+GC group showed a later onset and
developed more serious illness than the other two groups, and only this
group showed persistent paralysis during the observation period.
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We next asked whether the EAE protection or enhancement was
associated with Th2 or Th1 bias of
MOG35–55-specific T cells. A shift in the Ab
isotype from IgG2a to IgG1 is an important hallmark of an in vivo bias
of an immune response from Th1 to Th2. We measured serum IgG1 and IgG2a
titers of anti-MOG35–55 Abs on day 30 after
first immunization. The control mice transferred with unpulsed APC
showed low titers of IgG1 and IgG2a to MOG35–55
(Fig. 8). Another control group
transferred with -GC-pulsed APC showed a slightly higher IgG1 titer
and a low IgG2a titer. In striking contrast, the mice transferred with
-GC-pulsed APC treated with anti-B7.2 showed a remarkable
elevation of IgG1 titer to MOG35–55. These
results demonstrate that the EAE-protective protocol was most effective
in inducing anti-MOG35–55 Ab, which is
predominated by the IgG1 isotype, consistent with a Th2 shift of
MOG35–55-specific T cells. In contrast, mice
transferred with -GC-pulsed APC treated with an agonistic
anti-CD40 did not cause significant elevation of
anti-MOG35–55 Ab.
Anti-MOG35–55 IgE could not be detected in any
of the samples.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-GC capable of stimulating
NK T cells in vivo. Because ligand-activated NK T cells exhibited
immunoregulatory activities in previous studies (25, 26, 27),
we expected that the disease could be modified by administration of
-GC. However, an injection of -GC modulated EAE in the wild-type
mice only slightly in the enhancement of cumulative disease scores.
This result suggested that a mild Th1 biasing might be induced by
-GC injection. Subsequent experiments demonstrated that the effect
of -GC could be more sharply demonstrated in cytokine KO mice.
Although EAE in IL-4 KO mice was enhanced by -GC, the disease in
IFN- KO mice was suppressed by the glycolipid. Namely, IL-4 would
mask the disease-enhancing effect of -GC, but IFN- may hinder the
disease-protective effect of -GC. This observation suggests that the
balance between IFN- and IL-4 produced by NK T cells is critical in
the regulation of EAE.
Subsequently, we sought a way to control the cytokine profile of NK T
cells in wild-type mice. We focused on the role of costimulatory
molecules and performed experiments using -GC-pulsed APC of which
the expression of B7.1 or B7.2 molecule was blocked with Ab. We found
that stimulation of NK T cells with the GC-pulsed, B7.2-blocked APC
induced a Th2 bias of NK T cells in vitro and inhibited the development
of EAE in vivo. In contrast, stimulation of NK T cells with another APC
preparation (-GC-pulsed, CD40-activated APC) induced a Th1 bias of
NK T cells in vitro and augmented EAE in vivo. In addition, EAE
suppression was associated with an elevation of
anti-MOG35–55 IgG1 Ab corresponding to a Th2
bias of anti-MOG35–55 T cells. The
suppressive effect of the APC preparation was mediated by NK T cells,
as EAE in NK T KO mice was not altered by the APC treatment. Taken
together, we propose that ligand-activated NK T cells could exhibit
differential regulatory functions depending on its cytokine
phenotype.
The Th1/Th2 phenotype can be altered in conventional T cells by
blocking costimulatory pathways or stimulation with altered peptide
ligands (32, 34, 35). On the other hand, it is known that
B7/CD28 and CD40 ligand/CD40 interactions are required for full
stimulation of mouse NK T cells by -GC (14, 29) and
that CD161 molecule is a critical costimulatory molecule for human NK T
cells (36). The present study is the first to report that
the Th0-like phenotype of mouse NK T cells can be biased toward Th2
when they are stimulated with -GC in the absence of the B7.2-CD28
interaction. Moreover, we showed that altering the cytokine phenotype
of NK T cells could be a rational strategy for control of autoimmune
diseases. In fact, NK T cells are an attractive target for human
diseases because they recognize the same glycolipid in the context of
monomorphic CD1d regardless of the heterogeneous MHC background. Of
note, the administration of -GC-pulsed, B7.2-blocked APC is not the
only way to shift the Th1/Th2 balance of NK T cells. We may find a
therapeutic -GC homologue in the future that can efficiently switch
the cytokine balance.
This study has not answered whether or not B7.2 blockade is unique in inducing a Th2 shift of NK T cells. Although B7.1 blockade did not change the cytokine profile, our preliminary data showed that a combination of B7.1 and B7.2 blockade induced a more striking Th2 shift than blocking B7.2 alone and that anti-CD28 mAb induced a Th2 shift comparable with that induced by the combined B7.1 and B7.2 blocking (data not shown). This result could exclude the possibility that B7.1 and B7.2 costimulations play opposite or differential roles in the Th1/Th2 shift of NK T cells. The frequency of B7.1+ cells in spleen lymphoid cells is lower than that of B7.2+ cells (data not shown). Given this information, we speculate that blocking B7.1 and B7.2 shows additive effects, but blocking B7.1 costimulation alone may not reach the threshold for the switch of Th1/Th2 phenotype. The fine mechanism for the Th2 shift in the NK T cell phenotype needs to be further defined in the future. The Th1 shift of NK T cells induced by CD40-activated APC is also an interesting phenomenon that needs to be clarified. CD40-mediated APC activation has been shown to up-regulate B7.1 and B7.2 (37) and lead to an increased production of IL-12 (38). It is likely that up-regulation of costimulatory molecules and IL-12 may account for the Th1 shift of NK T cells and the EAE enhancement. However, since the activated APC would up-regulate a large set of molecules, it requires systemic analysis to define the molecular mechanism, which is beyond the scope of this study.
It is of note that the mice given -GC-pulsed CD40-activated APC
developed EAE much later than either of the other control groups. In
contrast, NK T KO mice tend to develop early-onset of EAE with a milder
clinical course (our manuscript in preparation). These results suggest
an unrecognized role of NK T cells for setting the timing of EAE onset.
A systematic study is required for better understanding the intriguing
observations.
-GC cannot be detected in mammalian tissue (14).
Therefore, it is presumed that NK T cells most probably recognize an
alternative CD1d-associated ligand(s) in physiological cellular
interactions. It is likely that the natural ligand has a lower affinity
for TCR than -GC and could be presented with weaker costimulatory
signals. If this is the case, NK T cells may exhibit Th0 or Th2
phenotype in natural immune regulation. On the other hand, numerical or
functional alteration of NK T cells is a feature of some autoimmune
diseases (39, 40, 41), although the underlying mechanism
remains unclear. An extreme shift of the NK T cells toward Th1 was
reported in type 1 diabetes (40). If we could
dedifferentiate the Th1-polarized NK T cells into the Th0 or could
inhibit the differentiation of NK T cells to Th1, the natural process
of the autoimmune disease might be significantly inhibited. The present
results indicate that abnormal expression of costimulatory molecules on
APC presenting a NK T cell ligand may lead to the cytokine bias of NK T
cells in autoimmune disease. Therefore, we speculate that reagents
useful for costimulation blockade (42, 43) not only
suppress T cell activation but may correct the cytokine bias of NK T
cells, thereby inducing therapeutic benefits. Further studies are in
progress to verify this postulate.
In summary, we demonstrate for the first time that ligand-activated NK T cells could exhibit differential cytokine profiles and opposing disease-modulating potentials, according to costimulatory signals provided by APCs. Although the role of NK T cells in autoimmunity has been questioned in some model systems (44, 45), our data imply that NK T cells could exhibit an immunoregulatory function when properly stimulated with their ligand.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Takashi Yamamura, Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan.
3 Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; NK, natural killer; -GC, -galactosylceramide; KO, knockout; MOG, myelin oligodendrocyte glycoprotein; PT, pertussis toxin.
Received for publication July 17, 2000. Accepted for publication September 27, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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14-J281 transgenic nonobese diabetic mice against diabetes. J. Exp. Med. 188:1831./-T cell receptor (TCR)+CD4-CD8- (NKT) thymocytes prevent insulin-dependent diabetes mellitus in nonobese diabetic (NOD)/Lt mice by the influence of interleukin (IL)-4 and/or IL-10. J. Exp. Med. 187:1047.14 NKT cells. Proc. Natl. Acad. Sci. USA 95:5690.14 natural killer T cells. J. Exp. Med. 190:783.-galactosylceramide directs conventional T cells to the acquisition of a Th2 phenotype. J. Immunol. 163:2373.-galactosylceramide polarizes CD1-reactive NK T cells towards Th2 cytokine synthesis. Eur. J. Immunol. 29:2014.[Medline]
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secretion of peripheral natural killer T cells in nonobese diabetic mice suggests new pathogenic mechanisms for insulin-dependent diabetes mellitus. J. Exp. Med. 190:963.This article has been cited by other articles:
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T. Osada, M. A. Morse, H. K. Lyerly, and T. M. Clay Ex vivo expanded human CD4+ regulatory NKT cells suppress expansion of tumor antigen-specific CTLs Int. Immunol., September 1, 2005; 17(9): 1143 - 1155. [Abstract] [Full Text] [PDF]
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 K. O. A. Yu, J. S. Im, A. Molano, Y. Dutronc, P. A. Illarionov, C. Forestier, N. Fujiwara, I. Arias, S. Miyake, T. Yamamura, et al. Modulation of CD1d-restricted NKT cell responses by using N-acyl variants of {alpha}-galactosylceramides PNAS, March 1, 2005; 102(9): 3383 - 3388. [Abstract] [Full Text] [PDF]
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N. Fukumoto, T. Shimaoka, H. Fujimura, S. Sakoda, M. Tanaka, T. Kita, and S. Yonehara Critical Roles of CXC Chemokine Ligand 16/Scavenger Receptor that Binds Phosphatidylserine and Oxidized Lipoprotein in the Pathogenesis of Both Acute and Adoptive Transfer Experimental Autoimmune Encephalomyelitis J. Immunol., August 1, 2004; 173(3): 1620 - 1627. [Abstract] [Full Text] [PDF]
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Y. Nagayama, K. Watanabe, M. Niwa, S. M. McLachlan, and B. Rapoport Schistosoma mansoni and {alpha}-Galactosylceramide: Prophylactic Effect of Th1 Immune Suppression in a Mouse Model of Graves' Hyperthyroidism J. Immunol., August 1, 2004; 173(3): 2167 - 2173. [Abstract] [Full Text] [PDF]
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D. E. Faunce, A. Terajewicz, and J. Stein-Streilein Cutting Edge: In Vitro-Generated Tolerogenic APC Induce CD8+ T Regulatory Cells That Can Suppress Ongoing Experimental Autoimmune Encephalomyelitis J. Immunol., February 15, 2004; 172(4): 1991 - 1995. [Abstract] [Full Text] [PDF]
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J. Schmieg, G. Yang, R. W. Franck, and M. Tsuji Superior Protection against Malaria and Melanoma Metastases by a C-glycoside Analogue of the Natural Killer T Cell Ligand {alpha}-Galactosylceramide J. Exp. Med., December 1, 2003; 198(11): 1631 - 1641. [Abstract] [Full Text] [PDF]
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S. Bedoui, S. Miyake, Y. Lin, K. Miyamoto, S. Oki, N. Kawamura, A. Beck-Sickinger, S. von Horsten, and T. Yamamura Neuropeptide Y (NPY) Suppresses Experimental Autoimmune Encephalomyelitis: NPY1 Receptor-Specific Inhibition of Autoreactive Th1 Responses In Vivo J. Immunol., October 1, 2003; 171(7): 3451 - 3458. [Abstract] [Full Text] [PDF]
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M. Araki, T. Kondo, J. E. Gumperz, M. B. Brenner, S. Miyake, and T. Yamamura Th2 bias of CD4+ NKT cells derived from multiple sclerosis in remission Int. Immunol., February 1, 2003; 15(2): 279 - 288. [Abstract] [Full Text] [PDF]
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M. A. Haque, T. Mizobuchi, K. Yasufuku, T. Fujisawa, R. R. Brutkiewicz, Y. Zheng, K. Woods, G. N. Smith, O. W. Cummings, K. M. Heidler, et al. Evidence for Immune Responses to a Self-Antigen in Lung Transplantation: Role of Type V Collagen-Specific T Cells in the Pathogenesis of Lung Allograft Rejection J. Immunol., August 1, 2002; 169(3): 1542 - 1549. [Abstract] [Full Text] [PDF]
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L. T. Mars, V. Laloux, K. Goude, S. Desbois, A. Saoudi, L. Van Kaer, H. Lassmann, A. Herbelin, A. Lehuen, and R. S. Liblau Cutting Edge: V{alpha}14-J{alpha}281 NKT Cells Naturally Regulate Experimental Autoimmune Encephalomyelitis in Nonobese Diabetic Mice J. Immunol., June 15, 2002; 168(12): 6007 - 6011. [Abstract] [Full Text] [PDF]
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M. S. Duthie and S. J. Kahn Treatment with {alpha}-Galactosylceramide Before Trypanosoma cruzi Infection Provides Protection or Induces Failure to Thrive J. Immunol., June 1, 2002; 168(11): 5778 - 5785. [Abstract] [Full Text] [PDF]
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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]
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V. Laloux, L. Beaudoin, C. Ronet, and A. Lehuen Phenotypic and Functional Differences Between NKT Cells Colonizing Splanchnic and Peripheral Lymph Nodes J. Immunol., April 1, 2002; 168(7): 3251 - 3258. [Abstract] [Full Text] [PDF]
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A. K. Singh, M. T. Wilson, S. Hong, D. Olivares-Villagomez, C. Du, A. K. Stanic, S. Joyce, S. Sriram, Y. Koezuka, and L. Van Kaer Natural Killer T Cell Activation Protects Mice Against Experimental Autoimmune Encephalomyelitis J. Exp. Med., December 17, 2001; 194(12): 1801 - 1811. [Abstract] [Full Text] [PDF]
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M. Maeda, S. Lohwasser, T. Yamamura, and F. Takei Regulation of NKT Cells by Ly49: Analysis of Primary NKT Cells and Generation of NKT Cell Line J. Immunol., October 15, 2001; 167(8): 4180 - 4186. [Abstract] [Full Text] [PDF]
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Z. Trobonjaca, F. Leithauser, P. Moller, R. Schirmbeck, and J. Reimann Activating Immunity in the Liver. I. Liver Dendritic Cells (but Not Hepatocytes) Are Potent Activators of IFN-{gamma} Release by Liver NKT Cells J. Immunol., August 1, 2001; 167(3): 1413 - 1422. [Abstract] [Full Text] [PDF]
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