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Immunobiology Section, Yale University School of Medicine, New Haven, CT 06520
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, because
none of these cell populations had detectable TNF-
production. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In vivo studies using different TCR transgenic (tg) mouse models have demonstrated that CD95 and TNF have partially redundant roles in the deletion of activated CD4+ T cells in lymphoid organs (8, 9). In contrast to information regarding the mechanisms of CD4+ T cell deletion, little is known about AICD in CD8+ T cells. In the previous study, we used a TCR tg mouse line recognizing SV40 T large Ag that was presented by the KK MHC class I molecule to shown that the injection of a specific peptide causes a massive peripheral deletion of CD8+ T cells. Interestingly, no apoptosis was observed in the lymph nodes or spleens, but CD8+ T cells disappeared from the circulating pool and accumulated transiently in the liver, where they underwent apoptosis (4). This observation has led to the conclusion that the liver is a specific site for the activation-induced apoptosis of CD8+ T cells.
Compared with peripheral lymphoid organs, the liver has a unique
anatomical environment that may be closely associated with its
immunologic function. In addition to the presence of large quantities
of resident macrophages (Kupffer cells), the liver contains
conventional T cells, NK cells, and especially NK-T cells at high
frequency (10, 11). These subpopulations have cytotoxicity against
virus-infected hepatocytes or tumor cells via CD95-dependent or
perforin-dependent pathways (12, 13, 14); these pathways are predominant
mechanisms of cell-mediated cytotoxicity. The cytotoxicity of these
cells can be augmented by cytokines such as IL-2 and IL-12, which have
an important role in antitumor immunity (13, 14, 15). However, the
immunoregulatory role of these cytotoxic cells remains largely
undefined. Recently, a novel cytokine, IL-18 has been identified and
cloned from cDNA extracted from the liver. This cytokine is produced by
Kupffer cells and has been shown to be a potent inducer of IFN-
production by T cells and a costimulatory factor for T cell activation
(16, 17). In addition, IL-18 augments NK cell activity in the spleen
and the liver (16, 13) as well as the cytotoxicity of Th1 cells (18),
suggesting that its role may be to regulate cytotoxicity. This evidence
prompted us to hypothesize that IL-18 may augment the killing activity
of intrahepatic cytotoxic cells during an immune response. In the
present study, we first tested whether IL-18 augments the cytotoxicity
of intrahepatic lymphocyte (IHL) subpopulations using an in vitro model
and found that IL-18 does indeed augment the killing activity of
different IHL subpopulations. In addition, the dependence of
cytotoxicity on CD95 or perforin was investigated in CD95 ligand
(CD95L)-deficient and perforin-deficient IHL subpopulations. The
implication of this observation in immunoregulation, particularly in
intrahepatic T cell deletion, is discussed here.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 (B6) and C57BL/6.C3Hgld/gld (gld) mice were obtained from The Jackson Laboratory (Bar Harbor, ME). Perforin-deficient (C57BL/6 x 129/SvEv, pfp KO) mice were purchased from Taconic (Germantown, NY). The mice were maintained in the Immunobiology Mouse Unit animal unit at Yale Medical School and were used once they reached 8 to 12 wk of age.
Reagents
Collagenase IV, DNase, and metrizamide were purchased from Sigma
(St. Louis, MO). Phycoerythrin-anti-NK1.1 Ab and
CyChrome-anti-mouse TCRß Ab were obtained from PharMingen (San
Diego, CA). Murine IL-18 was kindly provided by Dr. Haruki Okamura
(Hyogo College of Medicine, Nishinomiya, Japan and Hayashibara
Biochemical Laboratories (Okayama, Japan). An ELISA kit for
murine TNF- was purchased from Endogen (Woburn, MA).
Cell preparation
IHLs were isolated by perfusion via the portal vein with 5 ml of
Bruffs medium containing 0.2 mg/ml collagenase, 0.02 mg/ml DNase, and
5% FCS (digestion buffer). After perfusion, we homogenized the livers
by forcing them through a metal strainer; the livers were then digested
with 10 ml of digestion buffer at 37°C for 45 min. The majority of
the hepatocytes were removed by centrifugation at 30 x
g for 3 min. The supernatant was centrifuged at 650 x
g for 10 min to obtain a pellet of nonparenchymal cells. The
pellet from each liver was suspended with Bruffs medium to a final
volume of 1 ml before mixing with 4 ml of 30% metrizamide in PBS. The
cell suspension in metrizamide was underlaid with serum-free Bruffs
medium and centrifuged at 1500 x g for 20 min. The
cells at the interface were collected, washed with PBS, and counted. To
isolate NK cells, NK-T cells, and conventional T cells, total IHLs were
stained with phycoerythrin-anti-NK1.1 and
CyChrome-anti-mouse TCRß Abs and then sorted into
NK1.1+,TCRß+ (NK-T cells);
NK1.1+,TCRß- (NK cells); or
NK1.1-,TCRß+ (conventional T cells) using
a FACStarplus (Becton Dickinson, Mountain View, CA).
Similarly, spleen cells were sorted into TCRß+ cells
after staining the TCRß+ cells with
CyChrome-anti-mouse TCRß Ab. The purity of the sorted cells
was always >98%.
Cytotoxicity assay
Varying numbers of effector cells were stimulated with IL-18 at a concentration of 50 ng/ml in the presence of immobilized anti-mouse CD3 Ab (5 µg/ml) in a volume of 100 µl for 3 days. In the case of NK cells, the induction of cytotoxicity was performed by culturing cells alone or with IL-18 for 2 days. Cells from the human T leukemia cell line, Jurkat, or the mouse lymphoma cell line, YAC-, were labeled with Na251CrO4 (51Cr) for 1 h at 37°C, washed three times, and resuspended in 5 x 104 cells/ml. A total of 100 µl of target cells were added to the effector cells and incubated for 4 h. The percentage of specific Na251CrO4 release was calculated as described previously (13). All cytotoxicity assays were performed in 96-well U-bottom microplates (Falcon, Becton Dickinson Labware, Franklin Lakes, NJ), and all cultures were set up in duplicate.
Measurement of cytokine production
IHL subpopulations were stimulated with anti-CD3 Ab in the
presence or absence of IL-18 as described above. The supernatant was
collected, and the production of TNF- and IFN- was measured using
an ELISA kit for murine TNF- or IFN-.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To investigate whether IL-18 has any effect on the cytotoxicity of
liver killer cells, total IHLs were isolated from wild-type B6 mice and
stimulated with immobilized anti-CD3 Ab alone or in combination
with IL-18 for 3 days. The cytotoxicity was determined on a human T
cell line, Jurkat, which is widely used as a target for CD95-mediated
cytotoxicity in both human and murine systems. As shown in Figure 1
A, IHLs from B6 mice that had
been stimulated with anti-CD3 Ab alone were cytotoxic against
Jurkat cells only at a high number of responding cells (4.5 x
104 cells/culture); however, increased killing activity was
observed after stimulation of the cells with anti-CD3 Ab plus
IL-18. To test whether this cytotoxic effect was due to a CD95-CD95L
interaction, we performed the same experiments on IHLs from
gld mice, which are mutants for CD95L. The cytotoxicity of
IHLs from gld mice was enhanced by IL-18 to an extent that
was similar to what we observed for B6 mice (Fig. 1B),
showing the existence of a CD95-independent killing mechanism. In
addition to the CD95-mediated cytotoxicity, the other predominant
cytotoxic effector mechanism was perforin stored in cytoplasmic
granules. Therefore, we subsequently addressed whether IL-18 can
augment the cytotoxicity of IHLs via a perforin-mediated pathway. This
possibility was tested by assaying the cytotoxicity of IHLs from
perforin-deficient mice. The results show that the cytotoxicity of IHLs
from this strain was significantly increased by stimulating cells with
IL-18 (Fig. 1C). Therefore, we conclude that IL-18 enhances
the cytotoxicity of IHLs. However, this increased cytotoxicity was not
simply due to a single mechanism mediated by either CD95L or perforin.
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Since IHLs are a mixed population that include not only
conventional T cells but also NK-T, NK, and Kupffer cells, we
subsequently investigated which cell populations were responsible for
the IL-18-enhanced cytotoxicity. NK-T, NK, or conventional T cells were
sorted by FACS, and the purity of each population was always >98%
(data not shown). We initially tested whether conventional T cells in
the liver were cytotoxic and whether their cytotoxicity was regulated
by IL-18. Therefore, conventional T cells in the liver were tested for
their cytotoxicity just as IHLs were tested. None of the T cells from
B6 (Fig. 2A), gld,
or perforin-deficient mice (data not shown) showed any killing activity
against Jurkat cells, regardless of whether IL-18 was added. In
contrast, IL-18 significantly augmented the cytotoxicity of spleen
TCRß+ T cells that had been stimulated in the same way
(Fig. 2B). This result indicates that
anti-CD3-stimulated liver T cells are not cytotoxic, and no
cytotoxicity was induced in these cells by costimulation with IL-18.
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NK-T cells are present at a high frequency in the liver; these
cells may exert their function in such a specialized location.
Therefore, we examined this population as effectors of cytotoxicity. As
shown in Figure 3A, NK-T cells
from B6 mice did not show any cytotoxicity when stimulated with
anti-CD3 Ab alone; however, a strong cytotoxicity was induced when
the cells were costimulated with IL-18. We observed similar results in
NK-T cells from gld mice (Fig. 3B), suggesting
that the IL-18-induced cytotoxicity of liver NK-T cells is not
CD95-dependent. To test whether this cytotoxic effect was mediated by
perforin, the same experiment was performed using NK-T cells from
perforin-deficient mice. However, no cytotoxicity was observed in NK-T
cells from this strain, regardless of whether IL-18 was added (Fig. 3C). This result shows that perforin is required for the
cytotoxicity of NK-T cells that have been stimulated by IL-18. Similar
results were obtained using the classic NK target, YAC-1 (data not
shown). Since obtaining sufficient NK-T cells from young mice (8 wk
old) was very difficult, especially from the perforin-deficient mice,
we were unable to perform the cytotoxicity assay at the same number in
the starting cultures of effector cells from each strain. However, our
results strongly suggest that liver NK-T cells develop
perforin-mediated cytotoxicity in response to TCR ligation and IL-18
costimulation. We also tested whether IL-18 alone enhances the
cytotoxicity of the liver NK-T cells from B6 mice, but no enhancing
effect was found when cells were stimulated with IL-18 alone (data not
shown).
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NK cells are also a highly cytotoxic population; their
cytotoxicity can be up-regulated by certain cytokines, such as IL-2 and
IL-12 (12, 13). Since these cells do not express a CD3-associated TCR,
we tested the effect of IL-18 on these cells using a different
protocol. As shown in Figure 4A, NK cells from B6 mice that
had been cultured alone for 2 days were not cytotoxic; however, these
cells became highly cytotoxic when IL-18 was present in the cultures.
This cytotoxic activity was absent when NK cells from gld
mice were used (Fig. 4B), showing that the cytotoxicity was
CD95L-dependent. In parallel, we tested the role of perforin in NK cell
cytotoxicity using NK cells from perforin-deficient mice. We could not
observe any cytotoxic activity of NK cells from this strain, either
constitutively or when stimulated with IL-18 (Fig. 4C). The
experiment was repeated three times with identical results. These data
suggest that this form of IL-18-induced NK cell cytotoxicity depends
upon both CD95 and perforin. However, according to all of the systems
examined to date, CD95 and perforin function as independent killing
mechanisms.
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production by IHL subpopulations
TNF- has been shown to induce the apoptosis of peripheral
CD8+ T cells in both in vitro and in vivo experiments.
However, there is no information about the effect of TNF- in
intrahepatic cytotoxicity. To investigate whether TNF- is a mediator
for the killing activity in the liver, we examined the TNF-
production by IHL subpopulations, including NK-T cells, NK cells, T
cells, and total IHLs, by ELISA. However, none of these cell
populations from B6 mice produced any detectable TNF-, nor was
production induced by IL-18 (Fig. 5A). The same results were
also observed in gld and perforin-deficient mice (data not
shown). As a positive control, we measured IFN- production from the
same culture of IHLs from B6 mice. IFN- production was greatly
enhanced by IL-18 (Fig. 5B). Since no subset of IHLs
produces TNF- under the influence of TCR ligation plus IL-18
costimulation, we have concluded that soluble TNF- was not a
mediator of cytotoxicity in our experimental system.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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At present, it is not clear whether CD8+ T cells undergoing AICD receive a lethal signal in the periphery and are simply trapped by the liver, or whether the liver traps activated T cells and deletes them through an intrahepatic cytotoxic mechanism (19). To clarify the mechanism of intrahepatic T cell deletion, we first investigated whether an intrahepatic killing mechanism exists. In the present study, we used an in vitro system that enabled us to assess clearly the function of distinct cell populations in the liver and demonstrated that IL-18, a Kupffer cell cytokine, plays an important role by augmenting the cytotoxicity of IHL subpopulations via multiple effector mechanisms.
Most interestingly, we found that IL-18 enhances the cytotoxicity of
NK-T cells via a perforin-dependent pathway. NK-T cells are an unique
population of T lymphocytes that coexpress intermediate levels of
TCRß and NK1.1, which are markers of the NKR-P1 family. In
contrast to the lymph node and spleen, in which there are only 1 to 2%
of NK-T cells, the liver contains 30% of this population, suggesting
that such cells may exert their functions in specialized locations (10, 11). However, the immunoregulatory function of this population,
especially in the liver, is largely unknown. To date, it has been shown
that thymic NK-T cells induce apoptosis in double-positive thymocytes
via a CD95-dependent mechanism (20). It has also been shown that liver
NK-T cells are potent effector cells against hepatic metastasis by
killing tumor cells upon IL-12 administration, but the effector
mechanism for this killing was not identified (15). In our experimental
system, we found that NK-T cells acquire potent cytotoxicity upon TCR
ligation and IL-18 costimulation; this cytotoxicity was mediated by
perforin, a molecule that is also important in CTL- and NK
cell-mediated cytotoxicity (21, 22, 23). Our result is the first evidence
indicating that NK-T cell cytotoxicity is mediated by perforin. This
observation provides new information with regard to understanding the
molecular mechanism for NK-T cell cytotoxicity. In our experiments,
stimulating the cells with immobilized anti-CD3 Ab alone did not
induce any cytotoxicity. This lack of cytotoxicity may be due to
insufficient numbers of effector cells, or because a signal through
only anti-CD3 is not sufficient for activating the cells. We found
that IL-18 can significantly activate NK-T cells in the presence of
anti-CD3 Ab, showing not only the cytotoxicity but also a dramatic
morphologic change (i.e., enlargement of the cell size), which is a
feature of activated cells (our unpublished observations). These
results show that IL-18 is a potent inducer of the cytotoxicity of NK-T
cells. We believe that this cytotoxicity may play a major role in the
intrahepatic killing of activated T cells.
In addition to NK-T cells, IL-18 also augments the cytotoxicity of liver NK cells in B6 mice. NK cells are defined as a potent cytotoxic population against virus-infected cells and tumor cells (12, 24). The function of NK cells as an immunoregulatory cell has recently been reported. Arase et al. have shown that freshly isolated spleen NK cells expressing CD95L induce the death of CD95+ target cells (25). More recently, Tsutsui et al. have shown that IL-18 greatly enhances the CD95L expression and CD95L-mediated cytotoxicity on NK cell clones established from mouse liver (13). They also show that NK cell clones did not kill the YAC-1 cell line, which is a classic target for NK-mediated killing, even though they observed perforin expression in the cytoplasm. They suggest that, similar to CTLs, NK cells use only one of two distinct cytotoxic pathways, either the CD95L- or the perforin-mediated pathway. We found no cytotoxicity of NK cells from gld mice, suggesting that CD95L was the effector mechanism. However, NK cells from perforin-deficient mice also did not show any cytotoxicity, although CD95L should be intact in these animals. The requirement for CD95L and perforin for NK cell cytotoxicity was unexpected, but it is consistent with recent reports on the requirement of CD95L and perforin for the lysis of hepatocytes by CTL clones (26). The site of synergy between the Fas ligand- and perforin-induced cytotoxicity is currently under investigation. It is also possible that perforin gene expression is essential for NK cell maturation, with an impaired development of NK cells in perforin knockout mice. Regardless of the explanation, the data presented here confirm the observation of Tsutsui et al. that IL-18 enhances liver NK cell activity (13). We also used YAC-1 cells as targets (data not shown), but did not find any striking differences in YAC-1 sensitivity to the cytotoxicity by IHL subpopulations compared with Jurkat sensitivity. In particular, IHLs from perforin knockout mice were able to lyse YAC-1 cells. We also detected CD95 expression on the surface of YAC-1 (data not shown). Therefore, we conclude that YAC-1 cells are not a specific target for perforin-mediated cytotoxicity. Our results also demonstrated that Jurkat cells can be a sensitive target for perforin-mediated cytotoxicity.
The expression of both CD95 and CD95L results in the suicidal or fratricidal cell death of activated T cells (8). However, conventional T cells from the liver did not show any cytotoxicity when stimulated with anti-CD3 Ab, and the cytotoxicity was also not induced by IL-18. This finding is surprising, because it is widely accepted that T cells are major effectors in CD95-dependent cell death in peripheral lymphoid organs (7). The absence of cytotoxity suggests that T cells are not a major cytotoxic effector in the liver; therefore, the fratricidal death mechanism is not a cause for the intrahepatic killing of activated T cells. Rather, other cell populations such as NK-T and NK cells form the majority of the cytotoxicity in the liver. This result is in support of our observation in an in vivo model that the CD95-signaling pathway was not a major mechanism for intrahepatic CD8+ T cell deletion (W.Z.M. and I.N.C., manuscript in preparation).
Using TNF- receptor (TNFR)-deficient mice, Zheng et al. have shown
in an in vitro model that TNF- is involved in the apoptosis of
CD8+ T cells from lymph nodes (27). Subsequently, Speiser
et al. have used an in vivo model with TNFR-p55-deficient mice to show
that TNF is essential for the deletion of peripheral cytotoxic T cells
(28). However, they did not assess the role of TNF- in
intrahepatic T cell deletion. In our experiments, we could not detect
TNF- production by any subpopulations of IHLs; therefore, we
conclude that soluble TNF- is not a mediator of the cytotoxicity
mediated by NK-T, NK, or T cells in the liver. This conclusion
suggests that the liver and peripheral lymphoid organs may use
differential effector mechanisms for the deletion of activated T cells.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Tao Dao, Immunobiology Section, Yale University School of Medicine, New Haven, CT 06520.
3 Abbreviations used in this paper: AICD, activation-induced cell death; IHL, intrahepatic lymphocyte; tg, transgenic; CD95L, CD95 ligand; B6, C57BL/6; gld, C57BL/6.C3Hgld/gld.
Received for publication December 15, 1997. Accepted for publication May 4, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ß T cell receptor. J. Immunol. 151:1844.[Abstract]
/ß+ cells: new clues to their origin, specificity, and function. J. Exp. Med. 182:633.-inducing factor up-regulates Fas ligand-mediated cytotoxic activity of murine NK cell clones. J. Immunol. 157:3967.[Abstract]
ß T cells with intermediate TCR induced in the liver of mice by IL-12. J. Immunol. 154:4333.[Abstract]
production by T cells. Nature 378:88.[Medline]
-inducing factor (IGIF) is a costimulatory factor on the activation of Th1 but not Th2 cells and exerts its effect independently of IL-12. J. Immunol. 158:1541.[Abstract]
-inducing factor, a novel cytokine, enhances Fas ligand-mediated cytotoxicity of murine T helper 1 cells. Cell. Immunol. 173:230.[Medline]
/ß+ thymocytes against a CD4+8+ thymocyte population associated with intact Fas antigen expression on the target. J. Exp. Med. 180:423.This article has been cited by other articles:
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|
 |
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|
|
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 |
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|
|
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|
|
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|
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|
|
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|
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|
|
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|
|
|
|
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|
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|
|
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|
|
|
|
|
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|
|
|
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 |
|
 C A Dinarello Novel targets for interleukin 18 binding protein Ann Rheum Dis, November 1, 2001; 60(90003): iii18 - 24. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
T. Dao, M. Exley, W. Z. Mehal, S. M. A. Tahir, S. Snapper, M. Taniguchi, S. P. Balk, and I. N. Crispe Involvement of CD1 in Peripheral Deletion of T Lymphocytes Is Independent of NK T Cells J. Immunol., March 1, 2001; 166(5): 3090 - 3097. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
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T. L. Born, L. A. Morrison, D. J. Esteban, T. VandenBos, L. G. Thebeau, N. Chen, M. K. Spriggs, J. E. Sims, and R. M. L. Buller A Poxvirus Protein That Binds to and Inactivates IL-18, and Inhibits NK Cell Response J. Immunol., March 15, 2000; 164(6): 3246 - 3254. [Abstract] [Full Text] [PDF]
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S. Nakamura, T. Otani, Y. Ijiri, R. Motoda, M. Kurimoto, and K. Orita IFN-{gamma}-Dependent and -Independent Mechanisms in Adverse Effects Caused by Concomitant Administration of IL-18 and IL-12 J. Immunol., March 15, 2000; 164(6): 3330 - 3336. [Abstract] [Full Text] [PDF]
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J. S. Wild, A. Sigounas, N. Sur, M. S. Siddiqui, R. Alam, M. Kurimoto, and S. Sur IFN-{gamma}-Inducing Factor (IL-18) Increases Allergic Sensitization, Serum IgE, Th2 Cytokines, and Airway Eosinophilia in a Mouse Model of Allergic Asthma J. Immunol., March 1, 2000; 164(5): 2701 - 2710. [Abstract] [Full Text] [PDF]
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M. J. Smyth, K. Y. T. Thia, S. E.A. Street, E. Cretney, J. A. Trapani, M. Taniguchi, T. Kawano, S. B. Pelikan, N. Y. Crowe, and D. I. Godfrey Differential Tumor Surveillance by Natural Killer (NK) and NKT Cells J. Exp. Med., February 21, 2000; 191(4): 661 - 668. [Abstract] [Full Text] [PDF]
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M. C. Leite-de-Moraes, A. Hameg, A. Arnould, F. Machavoine, Y. Koezuka, E. Schneider, A. Herbelin, and M. Dy A Distinct IL-18-Induced Pathway to Fully Activate NK T Lymphocytes Independently from TCR Engagement J. Immunol., December 1, 1999; 163(11): 5871 - 5876. [Abstract] [Full Text] [PDF]
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W. Z. Mehal, A. E. Juedes, and I. N. Crispe Selective Retention of Activated CD8+ T Cells by the Normal Liver J. Immunol., September 15, 1999; 163(6): 3202 - 3210. [Abstract] [Full Text] [PDF]
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W. Hashimoto, T. Osaki, H. Okamura, P. D. Robbins, M. Kurimoto, S. Nagata, M. T. Lotze, and H. Tahara Differential Antitumor Effects of Administration of Recombinant IL-18 or Recombinant IL-12 Are Mediated Primarily by Fas-Fas Ligand- and Perforin-Induced Tumor Apoptosis, Respectively J. Immunol., July 15, 1999; 163(2): 583 - 589. [Abstract] [Full Text] [PDF]
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I. A. Khan, J. D. Schwartzman, L. H. Kasper, and M. Moretto CD8+ CTLs Are Essential for Protective Immunity Against Encephalitozoon cuniculi Infection J. Immunol., May 15, 1999; 162(10): 6086 - 6091. [Abstract] [Full Text] [PDF]
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