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*
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8603, Université René Descartes, Paris V, Hôpital Necker, Paris, France;
Institut National de la Santé et de la Recherche Unité 25, Hôpital Necker, Paris, France;
Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd., Gunma, Japan;
Core Research for Evolutional Science and Technology and Department of Molecular Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan; and
¶ 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 MethodsResults and DiscussionReferences |
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-galactosylceramide (-GalCer). The effect of IL-18 on IL-4
production by activated NKT cells took place both in vivo and in vitro
and was not affected by IL-12 which increased IFN-
secretion in the
same conditions. We show that NKT cells are the main targets for
IL-18-induced IL-4 production since it occurred neither in
NKT-deficient mice nor after stimulation of Th2 lymphocytes. Finally,
we provide evidence that the IL-4 promptly generated by NKT cells in
response to IL-18 plus -galactosylceramide in vivo can effectively
contribute to the adaptive Th2 immune response by up-regulating the
early activation marker CD69 on B cells. Our data support the notion
that, in contrast to the exclusive IFN- inducer IL-12, IL-18 acts in
a more subtle manner as a costimulatory factor in both pro-Th1 and
pro-Th2 responses depending on the nature of the stimulation and the
target cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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14-J281 chain,
preferentially associated with a V
8.2 chain (1, 2).
They are positively selected by the nonpolymorphic MHC class-I-like
molecule CD1d and recognize CD1d-bound lipid ligands
(1, 2, 3, 4). Because of the capacity of NKT lymphocytes to
promptly produce IL-4 upon TCR engagement, it has been proposed that
they participate in the differentiation of Th2 cells through this
biological activity (5, 6, 7). Moreover, it has been recently
reported that NKT cells, specifically activated by their cognate ligand
-galactosylceramide
(-GalCer),3 promote
the acquisition of a Th2 phenotype (8, 9).
The functional capacities of NKT cells depend on the cytokines present
in their microenvironment. In this line of evidence, we have
demonstrated that IL-7 is requisite for their optimal production of
IL-4 whereas IL-12, a proinflammatory cytokine, enhances their IFN-
production in response to TCR engagement, thus modifying the ratio of
IL-4:IFN- secreted by NKT cells (10, 11, 12, 13, 14). Furthermore,
we have recently established that, in the absence of TCR cross-linking,
IL-18, in association with IL-12, fully activates NKT lymphocytes to
produce IFN- and to kill target cells in a Fas ligand-dependent
manner (15).
IL-18 or IFN- inducing factor is a proinflammatory protein produced
by activated monocytes and dendritic cells as an inactive precursor
requiring cleavage by IL-1-converting enzyme/caspase 1 for its
maturation (16, 17, 18). IL-18 has been shown to share some of
the properties of IL-12, namely, its capacity to amplify IFN-
secretion by T, NK, and NKT cells (14, 15, 16). Moreover,
IL-18 is capable of enhancing GM-CSF production, cytotoxic activity as
well as Fas ligand expression, and exerts a significant antitumor
effect (15, 19, 20, 21, 22). In accordance with this potentiating
effect on cellular immune responses, it has been established that IL-18
synergizes in IL-12-driven Th1 development (23).
Unexpectedly, it was recently reported that IL-18 injection can promote
a preferential Th2 immune response in a murine model of diabetes
autoimmune or of allergic asthma (24, 25).
Considering these findings and our evidence for the responsiveness of
NKT cells to IL-18 (15), we investigated in the present
study whether IL-18 could modify the early IL-4 and/or IFN-
production by ligand-activated NKT cells and what were the
physiological implications of this biological activity.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Six- to 8-wk-old wild-type and mutant
(I-A-/-, CD1-/-, and
J281-/-) (26, 27, 28) C57BL/6 mice
were bred in our own facilities. RPMI 1640 (Life Technologies, Grand
Island, NY) supplemented with 10% heat-inactivated FCS (TechGen, Les
Ulis, France), 100 IU/ml penicillin, 100 µg/ml streptomycin, 10 mM
HEPES buffer (all from Life Technologies), and 5 x
10-5 M 2-ME was used as culture medium. Murine
IL-4, IL-12, IL-18, and IFN- were purchased from R&D Systems
(Abingdon, U.K.). Anti-IL-4 mAbs (11B11 and BVD6-24G2.3 clones),
anti-IFN- mAbs (AN18 and R46A2 clones), anti-TCR mAb
(clone H57-597), and anti-CD3 mAb (clone 145-2C11) were purified in
our laboratory. The BVD6-24G2.3 clone was obtained from DNAX (Palo
Alto, CA). The following mAbs used for cell depletion were purified in
our laboratory: CD8 (clone 53.67), B220 (clone RA3-6B2), and Mac1
(clone M1/70). Anti-CD4-PE (clone YTS 191.1), PE- or FITC-conjugated
anti-CD8 (clone YTS 169.4), anti-CD3-FITC (500-A2),
anti-TCR-FITC (clone H57-597), anti-IL-4-PE (clone
BVD-24G2), isotype controls, and streptavidin-PE (SAV-PE) were
purchased from Caltag (Le Perray en Yvelines, France). Biotinylated
anti-NK1.1 (clone PK136), anti-CD69 (clone H1.2F3),
anti-CD4-APC (clone RM4-5), and streptavidin-Cy-Chrome
(SAV-Cy-Chrome) were purchased from PharMingen (San Diego, CA); and
anti-rat Ig-coated magnetic beads were obtained from Dynal
(Compiègne, France).
Stimulation of TCR+NK1.1+ lymphocytes
Freshly isolated thymocytes or splenocytes were enriched for
CD4+ and
CD4-CD8- T cells by
depleting CD8, Mac1, and B220 cells labeled with the corresponding mAbs
and with anti-rat Ig-coated magnetic beads. The enriched lymphocyte
population was further incubated with anti-TCR and
anti-NK1.1 mAbs. Both
TCR+NK1.1+ and
TCR+NK1.1- cells
were sorted using a FACSVantage sorter (Becton Dickinson, Mountain
View, CA). Purity was >98% after reanalysis.
In some experiments, freshly isolated splenocytes were incubated for 45 min with anti-CD4-coated magnetic beads (Miltenyi Biotec, Bergisch-Gladbach, Germany) and positively sorted on a MACS-positive selection column. Enriched CD4+ splenocytes were further incubated with anti-NK1.1 and anti-CD4 mAb and CD4+NK1.1+ cells were sorted using a FACSVantage sorter. Purity was >98% after reanalysis.
Sorted lymphocytes were then stimulated at a concentration of 5 x
105 cells/ml with coated anti-CD3 mAb (10
µg/ml) or -GalCer at 100 ng/ml (Kirin Brewery Co., Ltd., Gunma,
Japan) (29) with 5 x 104
irradiated (20 Gy) autologous total spleen cells/ml with or without
IL-18 (100 ng/ml). In some experiments, sorted NKT cells were
stimulated with coated anti-CD3 mAb with or without IL-18 (100
ng/ml) or IL-12 (10 ng/ml) or both. Forty-eight hours later,
supernatants were harvested and stored at -80°C until IL-4 and
IFN- assays. The remaining cells were resuspended in 200 µl of
culture medium and pulsed for 18 h with 1 µCi of
[3H]thymidine. Cells were then harvested, and
thymidine uptake was assessed using a beta counter (LKB Wallac, St.
Quentin-en Yvelines, France).
Flow cytometric analysis
Cells were stained in PBS containing 2% FCS and 0.01 M sodium
azide and incubated for 30 min with appropriate dilutions of various
mAbs coupled to biotin, PE, allophycocyanin, or fluorescein. When mAbs
were biotinylated, SAV-PE or SAV-Cy-Chrome was used as a second step
reagent. For intracellular IL-4 staining, stimulated
TCR+NK1.1+ cells were
permeabilized and labeled as described previously (12). In
some experiments, the cell cycle was analyzed using propidium iodide
staining as previously described (30).
In another series of experiments,
TCR+NK1.1+
splenocytes were incubated with 0.5 µM CFSE (Molecular Probes,
Leiden, The Netherlands) at 37°C for 5 min. Labeled cells were washed
and then stimulated with coated anti-CD3 with or without IL-18 (100
ng/ml). After different periods of incubation, they were washed in PBS
and analyzed for proliferation.
Dead cells were excluded on the basis of forward and side scatter. At least 104 live lymphoid cells were acquired in each run. Samples were analyzed on a FACScalibur (Becton Dickinson).
In vivo treatment
Mice received a single injection of 2 µg of -GalCer (1 µg
i.v. plus 1 µg i.p. or 2 µg i.v.) with or without 1 µg of IL-18
(i.v.) dissolved in PBS containing 0.025% polysolvate 20 or vehicle
alone and were sacrificed at different time points. Sera were prepared
and frozen until cytokine assays. Splenocytes were cultured at 5
x 106 cells/ml without further stimulation.
Supernatants were collected 2 h later. In some experiments, mice
were i.p. injected with 500 µg of anti-IL-4 mAb (11B11) or
anti-IFN- (R46A2) 24 and 1 h before treatment with
-GalCer (2 µg/mouse).
Th1 and Th2 differentiation
Purified CD4+ splenocytes from
J281-/- mice were stained for CD62L and CD44
markers. Naive CD44-CD62L+
cells were sorted and then stimulated at a concentration of 2 x
105 cells/ml in 24-well culture plates coated
with anti-TCR mAb plus IL-2 (50 U/ml) in the presence of IL-4
(25 ng/ml) or IL-12 (20 ng/ml). Four days later, cells were harvested,
washed, and restimulated at a concentration of
105 cells/ml in 96-well microplates coated with
anti-TCR mAb in the presence of IL-7 (50 ng/ml), IL-18 (100
ng/ml), or medium alone. Supernatants were recovered 2 days later and
IL-4 and IFN- were measured.
IL-4 and IFN- assays
IL-4 and IFN- production was measured by ELISA as previously
described (6, 14). Samples were tested in duplicate and
the sensitivity of the ELISA was 40 pg/ml.
Statistics
Data were expressed as the means ± SD, and differences between means were evaluated using Student’s t test.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Our present study was designed to evaluate whether IL-18, a
pro-Th1 cytokine, could influence the cytokine profile generated by NKT
lymphocytes following an antigenic stimulation. For this purpose, we
sorted CD4+NK1.1+
splenocytes from MHC class II-deficient
(I-A-/-) C57BL/6 mice which are enriched for
NKT cells (31) and evaluated the effect of IL-18 on the
cytokine production by this subset in response to their specific Ag
-GalCer. Irradiated autologous total splenocytes were added as APCs
because the presentation of -GalCer to
CD4+NK1.1+ lymphocytes
requires CD1d molecules (32). Fig. 1
A clearly shows that
-GalCer-induced IL-4 production by
CD4+NK1.1+ splenocytes was
enhanced in the presence of IL-18. In the same conditions, IFN-
secretion was likewise increased (Fig. 1B), whereas neither
IL-4 nor IFN- were detected upon stimulation with IL-18 alone (data
not shown). These results indicate that IL-18 acts directly on
CD4+NK1.1+ lymphocytes.
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production by NKT cells without
TCR cross-linking depended on IL-12 (15). For these
reasons, TCR+NK1.1+
splenocytes were stimulated with coated anti-CD3 mAb to avoid the
addition of APCs and thus the possible contribution of endogenous IL-12
to the effect of IL-18 on IL-4 production by NKT cells. Freshly
isolated TCR+NK1.1+
splenocytes substantially increased their IL-4 secretion when IL-18 was
present during anti-CD3 mAb stimulation (Fig. 2A). IL-12 was neither
required for this effect nor did exogenous IL-12 modify the production
of IL-4 in response to anti-CD3 plus IL-18 (Fig. 2A).
Conversely, it did effectively potentiate IFN- secretion by
anti-CD3-stimulated
TCR+NK1.1+
splenocytes (Fig. 2B), as previously described
(14), thus confirming its ability to stimulate NKT
lymphocytes. As shown in Fig. 2B, IL-18 also enhanced
IFN- production by anti-CD3-stimulated
TCR+NK1.1+ cells,
while the TCR+NK1.1-
population, which stands for conventional T splenocytes in this setup,
produced no detectable IL-4 (<40 pg/ml) in response to anti-CD3
alone or in combination with IL-18 (Fig. 2A). Fig. 2B shows that conventional
TCR+NK1.1-
splenocytes produced IFN- when stimulated by anti-CD3 mAb in the
presence of IL-18 plus IL-12, in agreement with previous reports
showing the synergistic effect of IL-18 and IL-12 on IFN-
production (15, 19). IL-18 likewise enhanced the capacity
of NKT cells isolated from the thymus to produce IL-4. Indeed, sorted
TCR+NK1.1+ thymocytes
stimulated with coated anti-CD3 or anti-CD3 plus IL-18 (100
ng/ml) produced 21 ± 4 and 40 ± 5 ng of IL-4 per 5 x
105 cells, respectively (results represent
means ± SD from three individual experiments).
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IL-18 enhances IL-4 production by NKT lymphocytes at a single-cell level
The enhanced IL-4 production by NKT cells promoted by IL-18 as
compared with anti-CD3 stimulation alone might result from
proliferation of cytokine-producing cells rather than increased
synthesis in each individual NKT cell. To test this possibility, we
compared the proliferative response of NKT splenocytes exposed to
anti-CD3 vs anti-CD3 plus IL-18. The latter induced only a
slight increase of thymidine uptake by
TCR+NK1.1+ cells
relative to anti-CD3 stimulation (95,000 vs 72, 800 cpm). Moreover,
it did not significantly enhance the frequency of cycling (S +
G2 + M)
TCR+NK1.1+
splenocytes in the same conditions (Fig. 3A). In another set of
experiments, we analyzed NKT cell proliferation using the fluorescent
dye CFSE, which is a means of quantifying cell divisions by flow
cytometry (35). Fig. 3B shows that the addition
of IL-18 to the anti-CD3 stimulation did not significantly augment
the frequency of
TCR+NK1.1+
splenocytes which had divided after 2 days of culture. Thus, all three
methods concorde to establish that the presence of IL-18 does not
amplify NKT cell proliferation in response to anti-CD3
cross-linking, suggesting that other mechanisms may account for the
effect of IL-18 on IL-4 production. For this reason, we examined
whether IL-18 modulated IL-4 production by
TCR+NK1.1+
lymphocytes on single-cell levels using intracellular staining with
anti-IL-4 mAb. As shown in Fig. 4, the addition of IL-18 to the anti-CD3 mAb increased the percentage
of IL-4+ cells among
TCR+NK1.1+
splenocytes as well as the fluorescence intensity of the IL-4 staining,
proving that the effect was direct.
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B, a NF that has been implicated in the
transcription of IL-4 (36) and whose activation in
response to IL-18 and TCR cross-linking has been reported (23, 37). Alternatively, increased IL-4 production might also be
promoted by the nuclear AP-1, whose activation by IL-18 has been
suggested (38) and whose binding to the IL-4 promoter,
possibly in combination with other NFs, triggers IL-4 transcription
(39). IL-18 amplifies IL-4 production by NKT but not by Th2 lymphocytes
As illustrated in Fig. 2
, IL-18 did not affect
anti-CD3-induced IL-4 production by conventional
TCR+NK1.1- T cells
upon primary in vitro stimulation. This result is consistent with
previous studies showing that IL-18 cannot promote differentiation of
naive T cells into Th2 lymphocytes (23). Yet, it remained
possible that IL-18 could amplify this biological activity in
differentiated Th2 cells. To test this hypothesis, we cultured naive T
lymphocytes in pro-Th2 or pro-Th1 culture conditions, as previously
described (13), and further stimulated them with coated
anti-TCR mAb in the presence of IL-18, IL-7, or medium. IL-7 served
as a positive control, inasmuch as it can potentiate IL-4 production by
Th2 cells, as previously reported (13). Fig. 5A shows that IL-18, in
contrast to IL-7, did not modify the capacity of Th2 cells to generate
IL-4 upon TCR stimulation. It is likely that the loss of IL-18R
expression during Th2 differentiation, which has been documented
(40), is responsible for this unresponsiveness since IL-18
was active in this system, as assessed by the enhancement of IFN-
production by anti-TCR-stimulated Th1 cells (Fig. 5B). These data support the conclusion that IL-18 acts
specifically on NKT cells to augment their capacity to secrete IL-4
upon TCR engagement. Such an enhancing effect of IL-18 on Th2 cytokine
production has also been established for cell populations other than
NKT lymphocytes, namely, for IL-13 production by IL-2-activated NK and
T cells, and for both IL-4 and IL-13 production by IL-3-activated
basophils (41, 42).
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-GalCer-induced IL-4 production by NKT lymphocytes is amplified
by IL-18 in vivo
To address the question whether enhanced IL-4 production did also
occur in vivo, MHC class II-deficient mice received a single injection
of the specific NKT cell ligand -GalCer, IL-18, or both. Mice were
sacrificed 2 h later and splenocytes were cultured for 2 h
without further stimulation when IL-4 and IFN- were measured in cell
supernatants. Fig. 6A clearly
shows that coadministration of IL-18 and -GalCer resulted in a
2-fold increase of IL-4 production relative to -GalCer alone.
IFN- secretion was likewise increased in these conditions (Fig. 6B). In both cases,
TCR+NK1.1+
splenocytes were the targets of IL-18, as assessed by experiments with
NKT cell-deficient mice (CD1-/- and
J281-/- mutant strains) which produced
neither IL-4 nor IFN- after the same treatment (Fig. 6). In the
absence of -GalCer, injection of IL-18 or vehicle induced neither
IL-4 nor IFN- secretion whatever the strain used (Fig. 6). These
data suggest that IL-18 promptly enhances IL-4 production by activated
NKT lymphocytes. The potentiating effect of IL-18 on the very early
IL-4 production by ligand-activated
TCR+NK1.1+ cells was
further confirmed by the increased levels of IL-4 in the serum of
treated mice. Indeed, as early as 40 min after a single injection of
-GalCer, we detected higher levels of IL-4 in the serum of wild-type
mice treated with -GalCer plus IL-18 compared with -GalCer alone
(120 pg/ml and <40 pg/ml, respectively). The effect of IL-18 injection
on the serum IL-4 levels was still pronounced 60 min after injection
(570 vs 180 pg/ml -GalCer vs -GalCer plus IL-18 treatment). In
addition, using intracellular staining to detect IL-4 production on
single-cell levels, we observed that the effect of IL-18 on IL-4
production by
TCR+NK1.1+
splenocytes was already present 40 min after a single injection of
-GalCer (Fig. 7). These data clearly
show that IL-18 promptly acts in vivo on single NKT lymphocytes to
enhance their IL-4 production in response to their cognate Ag
-GalCer and that this enhancement is also observed in the serum.
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-GalCer treatment via endogenous IL-4 production
Finally, we addressed the question whether the newly generated
IL-4 could actually activate B cells. For this purpose, we examined the
expression of the early B cell activation marker CD69 whose
up-regulation by NKT cell-derived IL-4 induced by in vivo -GalCer
treatment has recently been established (43). As shown in
Fig. 8, the coinjection of IL-18
strikingly augmented the intensity of CD69 expression on the surface of
B cells in response to -GalCer, whereas vehicle or IL-18 alone had
no effect (Fig. 8). We further analyzed whether the effect of IL-18 on
the up-regulation of CD69 expression was dependent on endogenous IL-4.
To this end, mice were treated with blocking anti-IL-4 mAb before
-GalCer plus IL-18 injection. Fig. 8 shows that up-regulation of
CD69 expression on B cells was abrogated by anti-IL-4 treatment.
Anti-IFN- treatment had no such effect (Fig. 8). Taken together,
these results demonstrate that in vivo IL-18 treatment indirectly
enhances B cell activation through its capacity to amplify endogenous
IL-4 production by Ag-activated NKT lymphocytes.
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production by activated
NKT cells. However, in constrast to IL-4, which is the major inducer of
Th2 differentiation, IFN- alone is incapable of driving Th1
differentiation (22, 44). Thus, the presence of IFN-,
following IL-18 stimulation, probably does not prevent the development
of Th2 immune responses. It is therefore conceivable that, particularly
in the diabetes model, the pro-Th2 effect of IL-18 treatment results
from the capacity of IL-18 to promptly augment IL-4 production by NKT
lymphocytes. Indeed, the implication of NKT cells in the control of the
autoimmune disease in NOD mice was suggested by the demonstration
of their reduced number and function (11, 45) and by the
prevention of diabetes observed after infusion of NKT cell preparations
and in V14-J281-transgenic NOD mice (46, 47). In conclusion, our findings emphasize the complex immunomodulatory functions of IL-18 which are not restricted, as initially proposed, to the amplification of IL-12-driven Th1 differentiation (22), but can also promote Th2 differentiation by promptly enhancing IL-4 production by NKT lymphocytes. This novel biological activity of IL-18 provides further evidence for the importance of the microenvironment in determining the functional capacities of NKT cells.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Maria C. Leite-de-Moraes, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8603, Hôpital Necker, 161 rue de Sèvres, 75743 Paris, Cedex 15, France.
3 Abbreviations used in this paper: -GalCer, -galactosylceramide; SAV, streptavidin; NOD, nonobese diabetic; I-A, MHC class II deficient; CD1-/-, CD1d deficient; J281-/-, J281 deficient.
Received for publication May 22, 2000. Accepted for publication October 24, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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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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 I. Airoldi, L. Raffaghello, C. Cocco, R. Guglielmino, S. Roncella, F. Fedeli, C. Gambini, and V. Pistoia Heterogeneous Expression of Interleukin-18 and Its Receptor in B-Cell Lymphoproliferative Disorders Deriving from Naive, Germinal Center, and Memory B Lymphocytes Clin. Cancer Res., January 1, 2004; 10(1): 144 - 154. [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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T. Yoshimoto, B. Min, T. Sugimoto, N. Hayashi, Y. Ishikawa, Y. Sasaki, H. Hata, K. Takeda, K. Okumura, L. Van Kaer, et al. Nonredundant Roles for CD1d-restricted Natural Killer T Cells and Conventional CD4+ T Cells in the Induction of Immunoglobulin E Antibodies in Response to Interleukin 18 Treatment of Mice J. Exp. Med., April 21, 2003; 197(8): 997 - 1005. [Abstract] [Full Text] [PDF]
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P. Reddy, T. Teshima, G. Hildebrandt, D. L. Williams, C. Liu, K. R. Cooke, and J. L.M. Ferrara Pretreatment of donors with interleukin-18 attenuates acute graft-versus-host disease via STAT6 and preserves graft-versus-leukemia effects Blood, April 1, 2003; 101(7): 2877 - 2885. [Abstract] [Full Text] [PDF]
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 A. Metwali, A. Blum, D. E. Elliott, and J. V. Weinstock Interleukin-4 Receptor {alpha} Chain and STAT6 Signaling Inhibit Gamma Interferon but Not Th2 Cytokine Expression within Schistosome Granulomas Infect. Immun., October 1, 2002; 70(10): 5651 - 5658. [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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M. Okamoto, S. Kato, K. Oizumi, M. Kinoshita, Y. Inoue, K. Hoshino, S. Akira, A. N. J. Mckenzie, H. A. Young, and T. Hoshino Interleukin 18 (IL-18) in synergy with IL-2 induces lethal lung injury in mice: a potential role for cytokines, chemokines, and natural killer cells in the pathogenesis of interstitial pneumonia Blood, February 15, 2002; 99(4): 1289 - 1298. [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, S. Yara, K. Uezu, Y. Koguchi, M. Tohyama, M. Azuma, K. Takeda, S. Akira, and A. Saito Enhanced Gamma Interferon Production through Activation of Valpha 14+ Natural Killer T Cells by alpha -Galactosylceramide in Interleukin-18-Deficient Mice with Systemic Cryptococcosis Infect. Immun., November 1, 2001; 69(11): 6643 - 6650. [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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R. B. Smeltz, J. Chen, J. Hu-Li, and E. M. Shevach Regulation of Interleukin (IL)-18 Receptor {alpha} Chain Expression on CD4+ T Cells during T Helper (Th)1/Th2 Differentiation: Critical Downregulatory Role of IL-4 J. Exp. Med., July 16, 2001; 194(2): 143 - 154. [Abstract] [Full Text] [PDF]
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T. Hoshino, Y. Kawase, M. Okamoto, K. Yokota, K. Yoshino, K.-i. Yamamura, J.-i. Miyazaki, H. A. Young, and K. Oizumi Cutting Edge: IL-18-Transgenic Mice: In Vivo Evidence of a Broad Role for IL-18 in Modulating Immune Function J. Immunol., June 15, 2001; 166(12): 7014 - 7018. [Abstract] [Full Text] [PDF]
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R. Nishikomori, S. Gurunathan, K. Nishikomori, and W. Strober BALB/c Mice Bearing a Transgenic IL-12 Receptor {{beta}}2 Gene Exhibit a Nonhealing Phenotype to Leishmania major Infection Despite Intact IL-12 Signaling J. Immunol., June 1, 2001; 166(11): 6776 - 6783. [Abstract] [Full Text] [PDF]
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D. M. Walter, C. P. Wong, R. H. DeKruyff, G. J. Berry, S. Levy, and D. T. Umetsu IL-18 Gene Transfer by Adenovirus Prevents the Development of and Reverses Established Allergen-Induced Airway Hyperreactivity J. Immunol., May 15, 2001; 166(10): 6392 - 6398. [Abstract] [Full Text] [PDF]
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