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Department of Pathogenic Biochemistry, Research Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan;
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan;
Core Research for Evolutional Science and Technology of Japan Science and Technology Corporation, Tokyo, Japan; and
Department of Microbiology and Immunology, Howard Hughes Medical Institute, Vanderbilt University School of Medicine, Nashville, TN 37232
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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14 NKT cells produce large amounts of IFN-
and IL-4 upon
recognition of their specific ligand -galactosylceramide
(-GalCer) by their invariant TCR. We show here that NKT cells
constitutively express CD28, and that blockade of CD28-CD80/CD86
interactions by anti-CD80 and anti-CD86 mAbs inhibits the
-GalCer-induced IFN- and IL-4 production by splenic V14 NKT
cells. On the other, the blockade of CD40-CD154 interactions by
anti-CD154 mAb inhibited -GalCer-induced IFN- production, but
not IL-4 production. Consistent with these findings, CD28-deficient
mice showed impaired IFN- and IL-4 production in response to
-GalCer stimulation in vitro and in vivo, whereas production of
IFN- but not IL-4 was impaired in CD40-deficient mice. Moreover,
-GalCer-induced Th1-type responses, represented by enhanced
cytotoxic activity of splenic or hepatic mononuclear cells and
antimetastatic effect, were impaired in both CD28-deficient mice and
CD40-deficient mice. In contrast, -GalCer-induced Th2-type
responses, represented by serum IgE and IgG1 elevation, were impaired
in the absence of the CD28 costimulatory pathway but not in the absence
of the CD40 costimulatory pathway. These results indicate that
CD28-CD80/CD86 and CD40-CD154 costimulatory pathways differentially
contribute to the regulation of Th1 and Th2 functions of V14 NKT
cells in vivo. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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expressed on the majority
of NKT cells consists of a single invariant V14-J281 chain paired
preferentially with V8.2, V2, or V7, and recognizes glycolipid
Ags or particular hydrophobic peptides presented by the MHC class Ib
molecule CD1d (1, 2, 3). Although the physiological Ags for
NKT cells still remain unclear, -galactosylceramide
(-GalCer),3 a
glycolipid derived from a marine sponge, has been identified to act as
a specific ligand for V14 NKT cells (4, 5, 6). It has been
reported that -GalCer selectively stimulates V14 NKT cells to
rapidly produce large amounts of IFN- and IL-4 and to exhibit
cytotoxic and antitumor activities (7, 8). Moreover,
-GalCer-induced V14 NKT cell activation secondarily resulted in
the induction and modulation of innate (NK cell) and adaptive (T cell
and B cell) immune responses (9, 10, 11, 12, 13). The presentation of
-GalCer by CD1d expressed on certain APC, especially dendritic cells
(DC), efficiently induced V14 NKT cell activation (3, 4, 7, 14). It has been reported that CD40-CD154 interactions are
critically involved in the production of IFN- by
-GalCer-activated V14 NKT cells, which requires IL-12 production
by DC (15). On the other hand, V14 NKT cells also
produce large amounts of IL-4 in the primary response and have been
considered to play a role for the development of Th2 responses
(9, 10, 16, 17, 18, 19). Since IL-4 and IFN- have opposite
effects on Th1/Th2 development, the role for V14 NKT cells in the
regulation of immune responses remains controversial
(9, 10, 11). In the present study, we examined the involvement
of CD28- and CD40-mediated costimulatory pathways in IL-4 and IFN-
production by -GalCer-stimulated V14 NKT cells in vitro and in
vivo. We found differential contributions of these costimulatory
pathways to IL-4 and IFN- production by V14 NKT cells. Selective
manipulation of V14 NKT cell functions by -GalCer and the
blockade of costimulatory pathways, which can potentially modulate
systemic immune responses, is discussed. |
Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male C57BL/6 (B6) wild-type mice were purchased from Clear Japan (Tokyo, Japan). B6 CD28-deficient (CD28-/-) mice were originally purchased from The Jackson Laboratory (Bar Harbor, ME) and maintained in our animal facility. B6 CD1-deficient (CD1-/-) mice were generated as previously described (20). B6 CD40-deficient (CD40-/-) mice were kindly provided by H. Kikutani (Osaka University, Osaka, Japan) (21). All mice were maintained under specific pathogen-free conditions and used at 6–7 wk of age.
Reagents
-GalCer
[(2S,3S,4R)-1-o-(-D-galactopyranosyl)-2-(N-hexacosanoylamino)-1,3,4-octadecanetiol]
was provided by Y. Koezuka and K. Motoki (Kirin Brewery, Gumma, Japan)
and was prepared as described previously (4, 8). Purified
mAbs (no azide/low endotoxin grade) against mouse CD86 (PO. 3), CD154
(MR1), and IL-12 (C17.8) and control hamster IgG (A19-4) were purchased
from PharMingen (San Diego, CA). Control rat IgG was purchased from
Sigma (St. Louis, MO). The hybridoma-producing anti-mouse CD154 mAb
(MR1) was obtained from American Type Culture Collection (Manassas, VA)
(22). The hybridomas producing anti-mouse CD80 mAb
(RM80) and anti-mouse CD86 mAb (PO.3) were established in our
laboratory (23). The mAbs were prepared from these
hybridoma as described previously (23).
Flow cytometric analysis
Surface phenotype of the cells was characterized by three-color
flow cytometry as previously described (24). Briefly,
1 x 106 cells were first preincubated with
anti-CD16/32 (2.4G2) mAb to avoid the nonspecific binding of Abs to
FcR. Then the cells were incubated with a saturating amount of
biotinylated isotype-matched control mAbs (Ha4/8, A19-3, G235-2356, or
R3-34), anti-CD28 (37.51), anti-CD152/CTLA-4 (UC10-4F10-11),
anti-CD137/4-1BB (1AH2), anti-CD134/OX40 (OX86), anti-CD27
(LG.3A10), anti-CD30 (mCD30.1), and anti-CD154/CD40L (MR1) mAb
before incubation with FITC-conjugated anti-NK1.1 (PK136) mAb,
Cy-Chrome-conjugated anti-CD3
mAb (145-2C111), and PE-conjugated
streptavidin. All staining reagents were obtained from PharMingen.
After washing with PBS, the stained cells were analyzed on a
FACSCalibur (Becton Dickinson, San Jose, CA).
In vitro stimulation with -GalCer
Splenic mononuclear cells (MNC, 5 x
105) were cultured with 100 ng/ml -GalCer or
vehicle (0.1% DMSO) as a control in RPMI 1640 medium supplemented with
10% heat-inactivated FCS, 2 mM L-glutamine, and 25 mM
NaHCO3 in humidified 5%
CO2 at 37°C in 96-well U-bottom plates (Costar,
Cambridge, MA). In the blocking experiments, anti-CD80 (RM80),
anti-CD86 (PO.3), anti-CD154 (MR1), anti-IL-12 (C17.8), and
isotype-matched control mAbs were added at 10 µg/ml each in the
culture. After incubation for 72 h, the cell-free culture
supernatants were harvested to detect cytokine levels by ELISA.
ELISA
IFN- and IL-4 levels in the culture supernatants and
serum were evaluated using specific ELISA kits (Endogen, Boston, MA)
according to the manufacturer’s instructions. For serum IgG1- or
IgG2a-specific ELISA, microtiter plates (Immulon 2HB, 96-well; Dynex
Technologies, Chantilly, VA) were coated with monoclonal anti-IgG1
or anti-IgG2a (PharMingen) at 10 µg/ml in PBS overnight at 4°C.
The plates were blocked with PBS containing 1% BSA for 1 h and
washed extensively with 0.05% Tween 20 in PBS. Serial dilutions of
serum samples were incubated for 2 h at 37°C. The plates were
then washed with 0.05% Tween 20 in PBS and overlaid with
biotin-conjugated isotype-specific mAbs, including anti-mouse IgG1
(Serotec, Oxford, U.K.) and IgG2a (PharMingen), washed, and then
developed with a Vectastain ABC kit (Vector Laboratories, Burlingame,
CA) and o-phenylendiamine (Wako Pure Chemical, Osaka,
Japan). After termination of the reaction with 2 N
H2SO4, OD at 490/595 nm was
measured on a microplate reader (Bio-Rad, Hercules, CA). Concentrations
were calculated on the basis of standard curves of Ab isotypes
(PharMingen) run in parallel ELISA. Total serum IgE was quantitated by
IgE-specific sandwich ELISA as previously described
(25).
Cytotoxic assay
Cytolytic activity was assessed against NK-susceptible YAC-1
target cells and NK- and Fas ligand-resistant B16-BL6 cells by a
standard 51Cr release assay as previously
described (26, 27). Both target cells were cultured in
RPMI 1640 medium containing 10% FCS, 2 mM L-glutamine, and
25 mM NaHCO3. As effector cells, hepatic and
splenic MNC were isolated from the mice 24 h after i.p. injection
of 2 µg/200 µl of -GalCer or 200 µl of the vehicle (0.5%
polysorbate 20). Target cells (106) were labeled
with 100 µCi/ml
Na251CrO4
for 60 min at 37°C in RPMI 1640 medium containing 10% FCS. Labeled
target cells (104/well) were incubated in a total
volume of 200 µl with effector cells in 10% FCS-RPMI 1640 in 96-well
U-bottom plates. The plates were centrifuged before incubation, and
after 4 h the supernatant was harvested and counted in a gamma
counter. Specific lysis was calculated as previously described
(26, 27).
Experimental lung metastasis
Log-phase cell cultures of B16-BL6 were harvested with 1 mM EDTA
in PBS, washed three times with serum-free RPMI 1640, and
resuspended to appropriate concentrations in PBS. B16-BL6 cells
(5 x 104/100 µl) were injected i.v. into
syngeneic B6 mice, and then -GalCer (2 µg/200 µl) or 200 µl of
vehicle was i.p. administered on days 0, 4, and 8. On day 14, the
number of tumor colonies in the lung was counted under a dissecting
microscope.
Statistical analysis
Data were analyzed using a two-tailed Student t test. All p values < 0.05 were considered as significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To examine the expression of costimulatory receptors on
NKT cells, freshly isolated hepatic MNC from B6 mice were subjected to
three-color staining with biotin-conjugated mAb against CD28, CD152
(CTLA-4), CD27, CD30, CD134 (OX40), or CD137 (4-1BB), followed
by FITC-conjugated anti-NK1.1 mAb, Cy-Chrome-conjugated
anti-CD3 mAb, and PE-conjugated streptavidin. Then the expression
of each receptor was analyzed on electronically gated
NK1.1+ CD3+ (NKT),
NK1.1- CD3+ (T), or
NK1.1+ CD3- (NK) cells as
represented in Fig. 1
A. The
vast majority of NKT cells exhibited high levels of CD28 expression,
which was equivalent to that on conventional T cells (Fig. 1B). None of the other molecules were expressed by the cell
types that were examined. CD152 was not detected in NKT cells even by
the intracellular staining. Although most NK cells and T cells
expressed CD27, NKT cells did not express CD27. Similar results were
obtained for splenic NKT cells or hepatic and splenic NKT cells
isolated at 3 h after -GalCer injection (data not shown). These
results indicated a unique expression profile of costimulatory
receptors on NKT cells, which was apparently distinct from conventional
T cells and NK cells.
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and IL-4 production by -GalCer-stimulated NKT cells
We next investigated whether V14 NKT cells require
CD28-mediated costimulation for IFN- and IL-4 production in response
to their specific ligand, -GalCer. As shown in Fig. 2A, high levels of IFN- and
IL-4 were detected in the supernatant of splenic MNC when cultured with
-GalCer for 72 h. These cytokines were not detected when
splenic MNC from CD1-deficient mice were cultured with -GalCer,
indicating the dependence on CD1-restricted NKT cells as previously
reported (4, 12) (Fig. 2A). The blockade of
CD28-mediated costimulation by anti-CD80 and anti-CD86 mAbs
resulted in a marked but partial inhibition of IFN- production and
an almost complete inhibition (>95% in three experiments) of IL-4
production (Fig. 2A). Since it has been reported that IL-12
produced by DC plays a critical role in the -GalCer-induced IFN-
production (15) and that CD40-CD154 interactions are
required for the -GalCer-induced IL-12 production (28),
we also investigated the effect of blocking mAbs against CD154 and
IL-12. Rapid induction of CD154 on -GalCer-activated NKT cells was
confirmed in vitro (Fig. 2B) as previously reported
(28). Anti-CD154 mAb alone or anti-IL-12 mAb alone
inhibited IFN- production and conversely increased IL-4 production
by 2- to 2.5-fold (Fig. 2A). The combination of these two
mAbs did not result in further inhibition of IFN- production,
suggesting that the contribution of CD154 to IFN- production was
mediated by IL-12 as previously reported (15, 28). When
combined with anti-CD80/CD86 mAbs, anti-IL-12 further inhibited
IFN- production, whereas anti-CD154 mAb did not. This suggested
that the CD80/CD86-independent IFN- production, at least in part,
was IL-12 dependent but CD154 independent. Notably, anti-CD80/CD86
mAbs completely inhibited IL-4 production even in the presence of
anti-IL-12 or anti-CD154 mAb. Taken together, these results
indicated that the -GalCer-induced IFN- production by V14 NKT
cells was mostly dependent on both CD28-CD80/CD86 and CD154/CD40
costimulatory pathways, whereas IL-4 production was absolutely
dependent on the CD28-CD80/CD86 pathway but instead suppressed by the
CD154/CD40 pathway.
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-GalCer-induced IFN- production is impaired in both
CD28- and CD40-deficient mice, but IL-4 production is impaired in
CD28-deficient mice only
To confirm the differential contribution of CD28- and
CD40-mediated costimulatory pathways to IFN- and IL-4 production by
V14 NKT cells, we next investigated the -GalCer-induced IFN-
and IL-4 production by using splenic MNC from CD28- or CD40-deficient
mice. As represented in Fig. 3, splenic
MNC from CD28-deficient mice showed greatly impaired production of both
IFN- and IL-4 as compared with those from wild-type mice. Splenic
MNC from CD40-deficient mice showed similarly impaired IFN-
production but intact IL-4 production, which was comparable to
wild-type mice (Fig. 3). We also examined IFN- and IL-4 production
in vivo by administrating -GalCer into CD28- or CD40-deficient mice
(Fig. 4). In preliminary
experiments, we found that serum IFN-
levels peaked at 16 h and serum IL-4 peaked at 3 h after i.p.
injection of -GalCer to wild-type mice (data not shown). The serum
IFN- elevation at 16 h after -GalCer administration was
significantly impaired in both CD28- or CD40-deficient mice (Fig. 4).
The serum IL-4 elevation at 3 h after -GalCer administration
was abrogated in CD28-deficient mice but rather enhanced in
CD40-deficient mice (Fig. 4). No apparent shift in the kinetics of
serum IFN- and IL-4 levels was observed in these mutant mice (data
not shown). These results indicated that CD28-mediated costimulation
was required for both IFN- and IL-4 production by V14 NKT cells,
whereas CD40-mediated costimulation was only required for IFN-
production both in vitro and in vivo.
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-GalCer-induced cytolytic activity and
antimetastatic effect in CD28- and CD40-deficient mice
We next investigated the effect of CD28
or CD40 deficiency on -GalCer-induced cytotoxic activity of splenic
and hepatic MNC, which represents the Th1-like function of NKT cells,
since we have found that -GalCer-induced cytotoxicity and
antimetastatic activity were dependent on the IFN- produced by
-GalCer-activated V14 NKT cells and IFN--activated NK
cells.4 As reported (8), i.p.
injection of -GalCer into wild-type mice induced substantial
cytotoxic activities of splenic and hepatic MNC against both
NK-susceptible YAC-1 and NK-resistant B16-BL6 target cells (Fig. 5). These cytotoxic activities were
diminished by NK cell depletion by anti-asialo GM1 Ab
administration4 (data not shown). In contrast,
such an -GalCer-induced cytotoxic activity was not observed in
splenic or hepatic MNC from CD28- or CD40-deficient mice (Fig. 5). Then
we examined the antimetastatic effect of -GalCer in an experimental
lung metastasis model of the B16-BL6 melanoma, which is mediated by
V14 NKT cells (8). As previously reported
(8), -GalCer administration greatly reduced the lung
metastasis of B16-BL6 melanoma cells in wild-type mice (Fig. 6). In contrast, no significant
antimetastatic effect of -GalCer was observed in CD28-, CD40- (Fig. 6), or IFN--deficient mice (data not shown).4
These results indicated that both CD28- and CD40-mediated costimulatory
pathways were required for the Th1-like functions of V14 NKT cells
in vivo.
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-GalCer-induced Th2-like functions of NKT cells in vivo
It has been also reported that -GalCer administration
biases the subsequent immune responses toward Th2 type, as represented
by enhanced IgE and IgG1 production, which is mediated by IL-4 secreted
from V14 NKT cells (9, 10). We therefore investigated
the contribution of CD28 and CD40 costimulatory pathways to
the development of -GalCer-induced Th2-type immune responses in
vivo. As shown in Fig. 7A,
administration of -GalCer significantly increased the serum IgE and
IgG1 levels and conversely reduced the IgG2a level in wild-type mice as
previously reported (10). In contrast, no significant
elevation of serum IgE and IgG1 levels or reduction of the IgG2a level
was observed in CD28-deficient mice, indicating that the Th2-like
function of -GalCer-stimulated V14 NKT cells required
CD28-mediated costimulation. In CD40-deficient mice, administration of
-GalCer induced marginal but significant elevation of serum IgE and
IgG1 levels, suggesting that CD40 was not essential for this response.
The impaired elevation of serum IgE and IgG1 levels in CD40-deficient
mice as compared with wild-type mice appeared to result from the defect
in Ig class switching of CD40-deficient B cells in a later stage of the
response. To minimize the effect of CD40 deficiency on the later stage,
we administered anti-CD154 mAb only once before the administration
of -GalCer into wild-type mice. As shown in Fig. 7B,
anti-CD154 mAb significantly enhanced the elevation of serum IgE
and IgG1 levels after -GalCer administration. This suggested that
the CD154-CD40 interaction played a suppressive role in the
-GalCer-induced and V14 NKT cell-mediated Th2-type response
in vivo.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-4 by V14 NKT cells in
response to their specific ligand -GalCer. Consequently, blockade of
the CD28-mediated costimulation resulted in impairment of both Th1- and
Th2-type responses (serum IFN- and IL-4 elevation, cytotoxicity
induction, antimetastatic effect, and serum IgE/IgG1 elevation) induced
by -GalCer administration in vivo. In contrast, blockade of the
CD40-CD154 interaction inhibited only the -GalCer-induced Th1-type
responses (serum IFN- elevation, cytotoxicity induction, and
antimetastatic effect) but rather enhanced the Th2-type responses
(serum IL-4 elevation and serum IgE/IgG1 elevation). These results
indicate that Th1- and Th2-like functions of V14 NKT cells are
differentially regulated by CD28- and CD40-mediated costimulatory
pathways.
It has been well established that conventional T cells require a
costimulatory signal, in addition to Ag-specific TCR-mediated signal,
for their full activation (29). Such a
costimulatory signal can be commonly transmitted by CD28 or some
members of the TNF receptor superfamily, including CD27, CD30, CD134,
and CD137, in conventional T cells (29, 30, 31, 32, 33, 34). It was also
reported that CD161 transmitted a costimulatory signal into V24 NKT
cells (35). We here showed that NKT cells also express
CD28, which played a critical role in full activation of V14 NKT
cell functions as manifested by IFN- and IL-4 production. It has
been also reported that engagement of CD28 on NK cells promoted their
proliferation, IFN- production, and cytolytic activity (36, 37). Therefore, CD28 appears to play important roles not only in
adaptive immunity mediated by conventional T cells but also in innate
immunity mediated by NK and NKT cells. It was notable that NKT cells
did not express CD27, which has been implicated in activation of T
cells and NK cells (38, 39) and T cell differentiation
(40). This may be due to the unique ontogeny of NKT cells,
which is distinct from conventional T cells (1, 2, 41).
It has been shown that IFN- production by V14 NKT cells in
response to -GalCer is predominantly mediated by IL-12 produced by
DC and requires CD154-CD40 interaction (15). Our present
observations that anti-IL-12 mAb or anti-CD154 mAb alone
strongly inhibited the -GalCer-induced IFN- production and that
these mAbs did not exhibit an additive inhibitory effect (Fig. 2
A) are consistent with this notion. However, we also
observed that the combination of anti-CD80/CD86 mAbs with
anti-IL-12 mAb additively inhibited the IFN- production. This
suggested that CD28-CD80/CD86 interactions regulate IFN- production
by NKT cells in an IL-12-independent manner at least partly. This
CD28-mediated IFN- production might be directly induced by
transcriptional regulation of the IFN- gene by
CD28-mediated signals as demonstrated in conventional T cells
(42). Moreover, the CD28-mediated pathway and the
CD40/IL-12-mediated pathway could interact mutually, since
CD28-mediated costimulation stabilizes expression of CD154 on T cells
(43, 44), and CD40-mediated activation up-regulates
CD80/CD86 expression on DC (45). This explains why the
IFN- production by -GalCer-stimulated V14 NKT cells was mostly
dependent on both CD28- and CD40-mediated costimulatory pathways.
In the present study, we observed that the induction of cytotoxic
activity in liver or splenic MNC and the antimetastatic effect of
-GalCer were abolished in both CD28- and CD40-deficient mice (Figs. 5 and 6). This paralleled with the impairment of IFN- production in
these mice (Fig. 4). Both IL-12 and IL-4 have been implicated in
cytolytic activation of V14 NKT cells (26, 27, 46). In
our present observation, however, both the cytolytic activation and
antimetastatic effect were abolished in CD40-deficient mice, which
exhibited rather increased serum IL-4 levels upon -GalCer
administration. These results suggested that the -GalCer-induced
cytolytic activity and antimetastatic effect were associated with the
production of IFN-, but not IL-4, by V14 NKT cells. Consistent
with this notion, these responses were largely abolished in
IFN--deficient mice.4 On the other hand, we
observed that the -GalCer-induced serum IgE and IgG1 elevation was
abolished in CD28-deficient mice but not in CD40-deficient mice (Fig. 7A), which paralleled with the serum IL-4 elevation in these
mice (Fig. 4). Treatment with anti-CD154 mAb at -GalCer
administration rather augmented this response (Fig. 7B).
These results indicated that Th2-like function of V14 NKT cells was
totally dependent on the CD28-mediated costimulation and rather
suppressed by the CD40-mediated pathway, possibly due to a suppressive
effect of IFN- on IgE/IgG1 production (47).
As represented in the present study, V14 NKT cells have been shown
to produce both Th1-type (IFN-) and Th2-type (IL-4) cytokines upon
stimulation with a specific ligand (-GalCer) or anti-CD3 mAb
(48, 49). Some recent studies have shown that -GalCer
treatment polarizes bystander immune responses toward a Th2 phenotype
possibly through IL-4 production by V14 NKT cells (9, 10), whereas another study reported polarization toward a Th1
phenotype through IFN- production by V14 NKT cells
(11). This discrepancy in the effects of -GalCer might
result from differences in dose, timing, and route of -GalCer
administration. Our present study suggests that such a Th1- or
Th2-polarizing function of V14 NKT cells can be selectively
modulated by the blockade of costimulatory pathways, as represented by
polarization toward a Th2 phenotype by the blockade of CD154-CD40
interaction, at -GalCer administration. Since NKT cells have been
implicated in innate immunity against pathogens (50),
antitumor responses (8, 51, 52), liver damage
(53), and autoimmune diseases (54, 55, 56, 57),
selective modulation of their functions with specific ligand and
costimulatory blockade may be useful for prophylaxis and therapy of
such diseases.
|
Acknowledgments |
|---|
-GalCer
and Dr. Hisaya Akiba for technical assistance and helpful
suggestions. |
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Kazuyoshi Takeda, Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
3 Abbreviations used in this paper: -GalCer, -galactosylceramide; MNC, mononuclear cells; DC, dendritic cells.
4 Y. Hayakawa, K. Takeda, H. Yagita, S. Kakuta, Y. Iwakura, L. V. Kaer, I. Saiki, and K. Okumura. Critical contribution of IFN- and NK cells, but not perforin-mediated cytotoxicity, to the antimetastatic activities of -galactosylceramide. Submitted for publication.
Received for publication December 4, 2000. Accepted for publication March 7, 2001.
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T. Kawamura, K. Takeda, H. Kaneda, H. Matsumoto, Y. Hayakawa, D. H. Raulet, Y. Ikarashi, M. Kronenberg, H. Yagita, K. Kinoshita, et al. NKG2A Inhibits Invariant NKT Cell Activation in Hepatic Injury J. Immunol., January 1, 2009; 182(1): 250 - 258. [Abstract] [Full Text] [PDF]
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D. V. Baev, S. Caielli, F. Ronchi, M. Coccia, F. Facciotti, K. E. Nichols, and M. Falcone Impaired SLAM-SLAM Homotypic Interaction between Invariant NKT Cells and Dendritic Cells Affects Differentiation of IL-4/IL-10-Secreting NKT2 Cells in Nonobese Diabetic Mice J. Immunol., July 15, 2008; 181(2): 869 - 877. [Abstract] [Full Text] [PDF]
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E. Germanov, L. Veinotte, R. Cullen, E. Chamberlain, E. C. Butcher, and B. Johnston Critical Role for the Chemokine Receptor CXCR6 in Homeostasis and Activation of CD1d-Restricted NKT Cells J. Immunol., July 1, 2008; 181(1): 81 - 91. [Abstract] [Full Text] [PDF]
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 H. Ito, K. Ando, T. Ishikawa, T. Nakayama, M. Taniguchi, K. Saito, M. Imawari, H. Moriwaki, T. Yokochi, S. Kakumu, et al. Role of V{alpha}14+ NKT cells in the development of Hepatitis B virus-specific CTL: activation of V{alpha}14+ NKT cells promotes the breakage of CTL tolerance Int. Immunol., July 1, 2008; 20(7): 869 - 879. [Abstract] [Full Text] [PDF]
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H. J. J. van der Vliet, R. Wang, S. C. Yue, H. B. Koon, S. P. Balk, and M. A. Exley Circulating Myeloid Dendritic Cells of Advanced Cancer Patients Result in Reduced Activation and a Biased Cytokine Profile in Invariant NKT Cells J. Immunol., June 1, 2008; 180(11): 7287 - 7293. [Abstract] [Full Text] [PDF]
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O. Akbari, P. Stock, E. H. Meyer, G. J. Freeman, A. H. Sharpe, D. T. Umetsu, and R. H. DeKruyff ICOS/ICOSL Interaction Is Required for CD4+ Invariant NKT Cell Function and Homeostatic Survival J. Immunol., April 15, 2008; 180(8): 5448 - 5456. [Abstract] [Full Text] [PDF]
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 A. Yamaura, C. Hotta, M. Nakazawa, L. Van Kaer, and M. Minami Human invariant V{alpha}24+ natural killer T cells acquire regulatory functions by interacting with IL-10-treated dendritic cells Blood, April 15, 2008; 111(8): 4254 - 4263. [Abstract] [Full Text] [PDF]
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D.-H. Kim, W.-S. Chang, Y.-S. Lee, K.-A Lee, Y.-K. Kim, B. S. Kwon, and C.-Y. Kang 4-1BB Engagement Costimulates NKT Cell Activation and Exacerbates NKT Cell Ligand-Induced Airway Hyperresponsiveness and Inflammation J. Immunol., February 15, 2008; 180(4): 2062 - 2068. [Abstract] [Full Text] [PDF]
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Y. Chung, R. Nurieva, E. Esashi, Y.-H. Wang, D. Zhou, L. Gapin, and C. Dong A Critical Role of Costimulation during Intrathymic Development of Invariant NK T Cells J. Immunol., February 15, 2008; 180(4): 2276 - 2283. [Abstract] [Full Text] [PDF]
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D. Torres, C. Paget, J. Fontaine, T. Mallevaey, T. Matsuoka, T. Maruyama, S. Narumiya, M. Capron, P. Gosset, C. Faveeuw, et al. Prostaglandin D2 Inhibits the Production of IFN-{gamma} by Invariant NK T Cells: Consequences in the Control of B16 Melanoma J. Immunol., January 15, 2008; 180(2): 783 - 792. [Abstract] [Full Text] [PDF]
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T. Shimaoka, K.-i. Seino, N. Kume, M. Minami, C. Nishime, M. Suematsu, T. Kita, M. Taniguchi, K. Matsushima, and S. Yonehara Critical Role for CXC Chemokine Ligand 16 (SR-PSOX) in Th1 Response Mediated by NKT Cells J. Immunol., December 15, 2007; 179(12): 8172 - 8179. [Abstract] [Full Text] [PDF]
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 Y.-J. Chang, J.-R. Huang, Y.-C. Tsai, J.-T. Hung, D. Wu, M. Fujio, C.-H. Wong, and A. L. Yu Potent immune-modulating and anticancer effects of NKT cell stimulatory glycolipids PNAS, June 19, 2007; 104(25): 10299 - 10304. [Abstract] [Full Text] [PDF]
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J. Okajo, Y. Kaneko, Y. Murata, T. Tomizawa, C. Okuzawa, Y. Saito, Y. Kaneko, T. Ishikawa-Sekigami, H. Okazawa, H. Ohnishi, et al. Regulation by Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase Substrate-1 of {alpha}-Galactosylceramide-Induced Antimetastatic Activity and Th1 and Th2 Responses of NKT Cells J. Immunol., May 15, 2007; 178(10): 6164 - 6172. [Abstract] [Full Text] [PDF]
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L. Cheng, A. Ueno, S. Cho, J. S. Im, S. Golby, S. Hou, S. A. Porcelli, and Y. Yang Efficient Activation of V{alpha}14 Invariant NKT Cells by Foreign Lipid Antigen Is Associated with Concurrent Dendritic Cell-Specific Self Recognition J. Immunol., March 1, 2007; 178(5): 2755 - 2762. [Abstract] [Full Text] [PDF]
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C. Wahl, P. Bochtler, R. Schirmbeck, and J. Reimann Type I IFN-Producing CD4 V{alpha}14i NKT Cells Facilitate Priming of IL-10-Producing CD8 T Cells by Hepatocytes J. Immunol., February 15, 2007; 178(4): 2083 - 2093. [Abstract] [Full Text] [PDF]
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 M. Harada, K. Magara-Koyanagi, H. Watarai, Y. Nagata, Y. Ishii, S. Kojo, S. Horiguchi, Y. Okamoto, T. Nakayama, N. Suzuki, et al. IL-21-induced B{varepsilon} cell apoptosis mediated by natural killer T cells suppresses IgE responses J. Exp. Med., December 25, 2006; 203(13): 2929 - 2937. [Abstract] [Full Text] [PDF]
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J. S. Im, N. Tapinos, G.-T. Chae, P. A. Illarionov, G. S. Besra, G. H. DeVries, R. L. Modlin, P. A. Sieling, A. Rambukkana, and S. A. Porcelli Expression of CD1d Molecules by Human Schwann Cells and Potential Interactions with Immunoregulatory Invariant NK T Cells J. Immunol., October 15, 2006; 177(8): 5226 - 5235. [Abstract] [Full Text] [PDF]
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H. J. Kim, H. Y. Kim, B. K. Kim, S. Kim, and D. H. Chung Engagement of Glucocorticoid-Induced TNF Receptor Costimulates NKT Cell Activation In Vitro and In Vivo J. Immunol., March 15, 2006; 176(6): 3507 - 3515. [Abstract] [Full Text] [PDF]
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H. Kawamura, F. Aswad, M. Minagawa, S. Govindarajan, and G. Dennert P2X7 Receptors Regulate NKT Cells in Autoimmune Hepatitis J. Immunol., February 15, 2006; 176(4): 2152 - 2160. [Abstract] [Full Text] [PDF]
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S. Oki, C. Tomi, T. Yamamura, and S. Miyake Preferential Th2 polarization by OCH is supported by incompetent NKT cell induction of CD40L and following production of inflammatory cytokines by bystander cells in vivo Int. Immunol., December 1, 2005; 17(12): 1619 - 1629. [Abstract] [Full Text] [PDF]
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Y. Sen, B. Yongyi, H. Yuling, X. Luokun, H. Li, X. Jie, D. Tao, Z. Gang, L. Junyan, H. Chunsong, et al. V{alpha}24-Invariant NKT Cells from Patients with Allergic Asthma Express CCR9 at High Frequency and Induce Th2 Bias of CD3+ T Cells upon CD226 Engagement J. Immunol., October 15, 2005; 175(8): 4914 - 4926. [Abstract] [Full Text] [PDF]
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 O. Atochina and D. Harn LNFPIII/LeX-Stimulated Macrophages Activate Natural Killer Cells via CD40-CD40L Interaction Clin. Vaccine Immunol., September 1, 2005; 12(9): 1041 - 1049. [Abstract] [Full Text] [PDF]
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A. P. Uldrich, N. Y. Crowe, K. Kyparissoudis, D. G. Pellicci, Y. Zhan, A. M. Lew, P. Bouillet, A. Strasser, M. J. Smyth, and D. I. Godfrey NKT Cell Stimulation with Glycolipid Antigen In Vivo: Costimulation-Dependent Expansion, Bim-Dependent Contraction, and Hyporesponsiveness to Further Antigenic Challenge J. Immunol., September 1, 2005; 175(5): 3092 - 3101. [Abstract] [Full Text] [PDF]
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S. C. Yue, A. Shaulov, R. Wang, S. P. Balk, and M. A. Exley CD1d ligation on human monocytes directly signals rapid NF-{kappa}B activation and production of bioactive IL-12 PNAS, August 16, 2005; 102(33): 11811 - 11816. [Abstract] [Full Text] [PDF]
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T. Ota, K. Takeda, H. Akiba, Y. Hayakawa, K. Ogasawara, Y. Ikarashi, S. Miyake, H. Wakasugi, T. Yamamura, M. Kronenberg, et al. IFN-{gamma}-mediated negative feedback regulation of NKT-cell function by CD94/NKG2 Blood, July 1, 2005; 106(1): 184 - 192. [Abstract] [Full Text] [PDF]
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J. S. Bezbradica, A. K. Stanic, N. Matsuki, H. Bour-Jordan, J. A. Bluestone, J. W. Thomas, D. Unutmaz, L. Van Kaer, and S. Joyce Distinct Roles of Dendritic Cells and B Cells in Va14Ja18 Natural T Cell Activation In Vivo J. Immunol., April 15, 2005; 174(8): 4696 - 4705. [Abstract] [Full Text] [PDF]
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P. Gourdy, L. M. Araujo, R. Zhu, B. Garmy-Susini, S. Diem, H. Laurell, M. Leite-de-Moraes, M. Dy, J. F. Arnal, F. Bayard, et al. Relevance of sexual dimorphism to regulatory T cells: estradiol promotes IFN-{gamma} production by invariant natural killer T cells Blood, March 15, 2005; 105(6): 2415 - 2420. [Abstract] [Full Text] [PDF]
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 M. S. Duthie, M. Kahn, M. White, R. P. Kapur, and S. J. Kahn Both CD1d Antigen Presentation and Interleukin-12 Are Required To Activate Natural Killer T Cells during Trypanosoma cruzi Infection Infect. Immun., March 1, 2005; 73(3): 1890 - 1894. [Abstract] [Full Text] [PDF]
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G. Matsumoto, E. Kubota, Y. Omi, U. Lee, and J. M. Penninger Essential Role of LFA-1 in Activating Th2-Like Responses by {alpha}-Galactosylceramide-Activated NKT Cells J. Immunol., October 15, 2004; 173(8): 4976 - 4984. [Abstract] [Full Text] [PDF]
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K. Roelofs-Haarhuis, X. Wu, and E. Gleichmann Oral Tolerance to Nickel Requires CD4+ Invariant NKT Cells for the Infectious Spread of Tolerance and the Induction of Specific Regulatory T Cells J. Immunol., July 15, 2004; 173(2): 1043 - 1050. [Abstract] [Full Text] [PDF]
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Q. Xu, E. Goleva, L.-S. Ou, L.-B. Li, and D. Y. M. Leung CD56+ Cells Induce Steroid Resistance in B Cells Exposed to IL-15 J. Immunol., June 1, 2004; 172(11): 7110 - 7115. [Abstract] [Full Text] [PDF]
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Y. Yang, A. Ueno, M. Bao, Z. Wang, J. S. Im, S. Porcelli, and J.-W. Yoon Control of NKT Cell Differentiation by Tissue-Specific Microenvironments J. Immunol., December 1, 2003; 171(11): 5913 - 5920. [Abstract] [Full Text] [PDF]
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I. F. Hermans, J. D. Silk, U. Gileadi, M. Salio, B. Mathew, G. Ritter, R. Schmidt, A. L. Harris, L. Old, and V. Cerundolo NKT Cells Enhance CD4+ and CD8+ T Cell Responses to Soluble Antigen In Vivo through Direct Interaction with Dendritic Cells J. Immunol., November 15, 2003; 171(10): 5140 - 5147. [Abstract] [Full Text] [PDF]
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B. Gansuvd, W. J. Hubbard, A. Hutchings, F. T. Thomas, J. Goodwin, S. B. Wilson, M. A. Exley, and J. M. Thomas Phenotypic and Functional Characterization of Long-Term Cultured Rhesus Macaque Spleen-Derived NKT Cells J. Immunol., September 15, 2003; 171(6): 2904 - 2911. [Abstract] [Full Text] [PDF]
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Y. Hayakawa, S. Rovero, G. Forni, and M. J. Smyth {alpha}-Galactosylceramide (KRN7000) suppression of chemical- and oncogene-dependent carcinogenesis PNAS, August 5, 2003; 100(16): 9464 - 9469. [Abstract] [Full Text] [PDF]
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J. L. Matsuda, L. Gapin, J. L. Baron, S. Sidobre, D. B. Stetson, M. Mohrs, R. M. Locksley, and M. Kronenberg Mouse V{alpha}14i natural killer T cells are resistant to cytokine polarization in vivo PNAS, July 8, 2003; 100(14): 8395 - 8400. [Abstract] [Full Text] [PDF]
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G. Galli, S. Nuti, S. Tavarini, L. Galli-Stampino, C. De Lalla, G. Casorati, P. Dellabona, and S. Abrignani CD1d-restricted Help To B Cells By Human Invariant Natural Killer T Lymphocytes J. Exp. Med., April 21, 2003; 197(8): 1051 - 1057. [Abstract] [Full Text] [PDF]
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A. Chackerian, J. Alt, V. Perera, and S. M. Behar Activation of NKT Cells Protects Mice from Tuberculosis Infect. Immun., November 1, 2002; 70(11): 6302 - 6309. [Abstract] [Full Text] [PDF]
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Y. Hayakawa, K. Takeda, H. Yagita, M. J. Smyth, L. Van Kaer, K. Okumura, and I. Saiki IFN-gamma -mediated inhibition of tumor angiogenesis by natural killer T-cell ligand, alpha -galactosylceramide Blood, August 13, 2002; 100(5): 1728 - 1733. [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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M. J. Smyth, N. Y. Crowe, D. G. Pellicci, K. Kyparissoudis, J. M. Kelly, K. Takeda, H. Yagita, and D. I. Godfrey Sequential production of interferon-gamma by NK1.1+ T cells and natural killer cells is essential for the antimetastatic effect of alpha -galactosylceramide Blood, February 15, 2002; 99(4): 1259 - 1266. [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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K. Kawakami, Y. Kinjo, K. Uezu, S. Yara, K. Miyagi, Y. Koguchi, T. Nakayama, M. Taniguchi, and A. Saito Monocyte Chemoattractant Protein-1-Dependent Increase of V{alpha}14 NKT Cells in Lungs and Their Roles in Th1 Response and Host Defense in Cryptococcal Infection J. Immunol., December 1, 2001; 167(11): 6525 - 6532. [Abstract] [Full Text] [PDF]
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