International Immunology

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International Immunology, Vol. 13, No. 4, 459-463, April 2001
© 2001 Japanese Society for Immunology

NK cells and NKT cells collaborate in host protection from methylcholanthrene-induced fibrosarcoma

Mark J. Smyth, Nadine Y. Crowe^1, and Dale I. Godfrey^1,

Cancer Immunology, Peter MacCallum Cancer Institute, St Andrews Place, East Melbourne, Victoria 8006, Australia
¹ Department of Pathology and Immunology, Monash University Medical School, Prahran, Victoria 3181, Australia

Correspondence to: M. Smyth, Cancer Immunology, Peter MacCallum Cancer Institute, Locked Bag 1, A'Beckett Street, Victoria, Australia

	Abstract

Top Abstract Introduction Methods Results and discussion Concluding remarks References

 
NK1.1⁺ V14J281⁺ (NKT) cells can be induced by IL-12 therapy to mediate tumor rejection; however, methylcholanthrene (MCA)-induced fibrosarcoma is the only tumor model described where NKT cells play a natural role in controlling tumor initiation. From our previous study in C57BL/6 mice it remained unclear whether NK cells were also involved in this natural response. Herein, to discriminate the function of NK and NKT cells, we have evaluated fibrosarcoma development in mice deficient in NKT cells, but not NK cells, and mice deficient in NK cells, but not NKT cells. The results indicate that both NK cells and NKT cells are essential and collaborate in natural host immunity against MCA-induced sarcoma. In contrast, sarcoma incidence and growth rate were reduced using IL-12 therapy, this effect was mediated in the absence of T cells (including NKT cells), but not NK cells.

Keywords: immunotherapy, in vivo animal model, NK cell, NKT cell, tumor immunity

	Introduction

Top Abstract Introduction Methods Results and discussion Concluding remarks References

 
Chemical induction of tumors in inbred mice, particularly sarcomas induced by methylcholanthrene (MCA), has been a tumor model often used by immunologists to investigate immune surveillance (1). Treatment of mice with the powerful T and NK cell-stimulatory cytokine, IL-12, was shown to delay and reduce tumor appearance in MCA-inoculated mice (2). This study, and other studies using perforin (pfp)-deficient mice (3) and IFN- receptor-deficient mice (4), first defined the importance of immunological control, at the molecular level, on tumor induction by MCA.

Despite these advances, studies in nu/nu mice by Stutman (5) had demonstrated a similar tumor incidence compared with wild-type mice and thus controversy persisted concerning what cellular mechanisms regulated sarcoma induction by MCA. However, our recent study using TCRJ281^–/– mice specifically deficient for NKT cells defined that natural surveillance of MCA-induced sarcomas was controlled by these cells (6). This is the only tumor model described where NKT cells naturally regulate tumor initiation or growth, despite several studies that define the involvement of NKT cells in IL-12- or -galactosylceramide-mediated anti-metastatic activity (7,8). A difficulty with the aforementioned MCA study (6) was discriminating whether NK cells were additionally important in host protection, since anti-NK1.1 mAb depletes both NK and NKT cells. This is an important issue since it has remained unclear as to whether NKT cells can act alone as anti-tumor effector cells. Herein, we have taken advantage of the ability of anti-asialo-GM₁ antibody to deplete NK cells, but not NKT cells, to demonstrate that indeed both NK and NKT cell subsets collaborate to constitute protective natural anti-tumor immunity.

	Methods

Top Abstract Introduction Methods Results and discussion Concluding remarks References

 
Mice
Inbred C57BL/6 (B6), BALB/c and BALB/c.scid mice were purchased from the Walter and Eliza Hall Institute of Medical Research (WEHI; Melbourne, Australia). BALB/c.B6Cmv1^r (NK1.1⁺) were obtained from the Animal Resources Centre (Perth, Australia). The following gene-targeted mice were bred at the Austin Research Institute Biological Research Laboratories (ARI-BRL): C57BL/6.RAG-1-deficient (B6.RAG-1^–/–) mice (from Dr Lynn Corcoran, WEHI) (9) and C57BL/6 TCRJ281-deficient (B6.J281^–/–) mice (from Dr Masaru Taniguchi, Chiba University School of Medicine, Chiba, Japan) (6). Mice aged 6–12 weeks old were used in all experiments that were performed according to animal experimental ethics committee guidelines.

NK/NKT cell subset depletion
The protocols for depletion of NK1.1⁺ (NK and NKT) cells in B6 mice using anti-NK1.1 mAb (PK136) were as previously described (6,10). Groups of BALB/c and BALB/c.B6Cmv1^r (NK1.1⁺) mice were depleted of asialo-GM₁⁺ cells using 20 µl of the rabbit anti-asialo-GM₁ antibody (prepared as recommended; Wako Chemicals, Richmond, VA) on days –1, 0 (the day of MCA inoculation) and weekly thereafter. The BALB/c.B6Cmv1^r (NK1.1⁺) mice were used to show that this depletion was effective, since DX5 and other surrogate markers are not entirely suitable for detecting NKT cells (11). Anti-asialo-GM₁ antibody significantly depleted NK1.1⁺ TCRß^– NK cells, but not NKT cells in both C57BL/6 and BALB/c.B6Cmv1^r mice (Fig. 1). Assessment of depletion was performed following preparation of cell suspensions from spleen and liver as described (11). Flow cytometry of cells was performed with allophycocyanin-conjugated anti-ßTCR (clone H57-597), phycoerythrin-conjugated anti-NK1.1 (clone PK-136), FITC-conjugated anti-CD8a (clone 53.6.7) and biotin-conjugated anti-CD4 (clone CT-CD4; Caltag, Burlingame, CA). Streptavidin-conjugated PerCP was used to detect biotin-conjugated anti-CD4. Asialo-GM₁ expression was revealed using sheep anti-rabbit Ig–FITC. All flow cytometry reagents were purchased from PharMingen (San Diego, CA), unless otherwise indicated. Cells were isolated, gated and analyzed as previously described (11). To assess the maintenance of NKT cell function in anti-asialo-GM₁ antibody-treated mice, mice were treated i.v. with 1.5 µg of anti-mouse CD3 mAb (145-2C11) and serum collected 8 h later. Serum IFN- was measured by a mouse IFN--specific ELISA according to the manufacturer's protocol (PharMingen).

View larger version (44K): [in this window] [in a new window]   Fig. 1. NK cells are preferentially depleted by anti-asialo-GM1 treatment. (A and B) Liver lymphocytes were labeled with anti-NK1.1, -ßTCR and -asialo-GM1 (AGM1). AGM1 expression was revealed using sheep anti-rabbit Ig–FITC, and is shown on T (dashed line), NKT (solid line) and NK (shaded histogram) cells of the liver. Background staining by non-specific rabbit anti-sera is shown for whole liver lymphocytes (dotted line). (C and F). Groups of B6 and BALB/c.B6Cmv1r mice were injected with anti-asialo-GM1 or PBS and the spleen and liver harvested at days 1 and 6. Isolated lymphocytes were labeled with anti-NK1.1 and -ßTCR. The percentages of NK (C and E) and NKT (D and F) cells in the spleen (C and D) and liver (E and F) are shown. Results represent the mean ± SE, n = 3 unless otherwise indicated. (*P < 0.05, **P < 0.005, Mann–Whitney U-test).

 
Tumor surveillance in vivo
Effector function was examined in gene-targeted mice or mice depleted of lymphocyte subsets by inducing fibrosarcoma in mice using MCA as described (6). Anti-asialo-GM₁ or anti-NK1.1 mAb was administered on day –1, 0 (the day of MCA inoculation) and weekly thereafter. Mouse IL-12 was kindly provided by Genetics Institute (Cambridge, MA). The preparation of IL-12 was diluted in PBS immediately before use. Mice received 250 U of IL-12 i.p. 5 days a week for 20 weeks, in a schedule of 3 weeks on and 1 week off. Mice were weighed periodically during the first 120 days to determine any potential toxicity of IL-12. Relative sarcoma growth rate was calculated from the gradient of individual growth curves [plotted as s.c. tumor size – the product of two perpendicular diameters (cm²)]. The mean gradient of each group was standardized with the group of BALB/c mice receiving 100 µg MCA alone = 1.0.

	Results and discussion

Top Abstract Introduction Methods Results and discussion Concluding remarks References

 
Anti-asialo-GM₁ antibody depletes NK cells, but not NKT cells
Anti-asialo-GM₁ antibody is an effective means of depleting NK cells from a variety of mouse strains (12,13). Analysis of the specificity and effectiveness of this depletion has been difficult in BALB/c mice that lack the NK1.1 marker for suitable discrimination between NK cells and other T cell subsets. Since anti-NK1.1 mAb is the preferred reagent for staining NK and NKT cells, we have made use of the congenic BALB/c.B6.Cmv1^r strain (14) that expresses the NK1.1 allele. Asialo-GM₁ was shown to be expressed at significantly higher levels on liver NK1.1⁺TCRß^– cells than on NK1.1⁺TCRß⁺ or other TCRß⁺ cells (Fig. 1). A protocol of weekly injection of anti-asialo-GM₁ antibody was employed to treat BALBc and B6 mice inoculated with MCA. This same protocol was shown to maintain significant depletion of NK1.1⁺TCRß^– cells, but not NK1.1⁺TCRß⁺ or other TCRß⁺ cells, in both B6 mice and BALB/c.B6.Cmv1^r mice (Fig. 1). A lack of effect of anti-asialo-GM₁ antibody treatment on the function of NKT cells was confirmed by the elevated serum IFN- levels in these mice responding to anti-CD3 antibody (Fig. 2). Previous studies have indicated that NKT cells were the major T cell population responsible for IFN- production in response to TCR–CD3 ligation (15,16). Interestingly, our data also suggested that NK cells are not required for NKT cell-mediated IFN- production.

View larger version (16K): [in this window] [in a new window]   Fig. 2. Anti-asialo-GM1 antibody does not reduce IFN- production by anti-CD3 mAb-activated NKT cells. Untreated or anti-asialo-GM1 antibody-treated (day –6 or –1) B6 mice and B6.J281–/– mice were treated i.v. with 100 µl of PBS or 1.5 µg of anti-mouse CD3 mAb (145-2C11) and serum collected 8 h later. Serum IFN- was measured by a mouse IFN--specific ELISA. Serum of all PBS-treated mice did not contain detectable IFN- (<50 pg/ml). The results are recorded as the mean serum IFN- (pg/ml) ± SE for two mice performed in triplicate.

 
NK and NKT cells collaborate in host protection from MCA-induced fibrosarcoma
A clear picture of which host immune cells control sarcoma induction by MCA has been lacking. Our recent analysis using TCRJ281^–/– mice identified NKT cells to be critical for natural immunity against MCA-induced fibrosarcoma in the C57BL/6 mouse (6). However, previous depletion of NK1.1⁺ cells in B6 mice using the anti-NK1.1 mAb did not discriminate whether NK cells also played a role since both NK and NKT cells were eliminated by the protocol employed (6). Therefore, herein we compared the effect on MCA-induced sarcoma incidence in B6 mice when specifically depleting NK cells using anti-asialo-GM₁ antibody (Fig. 3). At either dose of MCA inoculated (100 or 25 µg), depletion of NK cells alone was sufficient to cause B6 mice to develop significantly more sarcomas. Susceptibility to sarcoma was equivalent in mice specifically lacking NKT cells (B6.J281^–/–) or NK cells (B6 + anti-asialo-GM₁), suggesting that both NK and NKT cells were indispensable for innate protection from MCA-induced sarcoma. No further increase in susceptibility has been observed in B6.J281^–/– mice depleted using anti-NK1.1 mAb (6). Increased susceptibility of B6.RAG-1^–/– mice (Fig. 3A) and B6.ß₂microglobulin^–/– mice (data not shown) was also consistent with the lack of NKT cells in these two strains (15–19).

View larger version (64K): [in this window] [in a new window]   Fig. 3. NK and NK cells collaborate in host protection from MCA-induced fibrosarcoma. Groups of (A) B6, B6.RAG-1–/– and B6.J281–/– or (B) BALB/c and BALB/c.scid mice were injected s.c. in the hind flank as indicated with 100, 25 or 5 µg MCA diluted in 0.1 ml corn oil. Some groups of B6 or BALB/c mice were also depleted of NK cells (+ anti-asGM1) or NK1.1+ cells (B6 + anti-NK1.1) in vivo. Mice were observed weekly for tumor development over the course of 50–180 days. Tumors >5 mm in diameter and demonstrating progressive growth over 3 weeks were counted as positive. Sarcoma development was recorded at 180 days as a percentage of the mice in each group (in parentheses). The number of mice in each group is shown in parentheses. Significant differences from (A) B6 mice or (B) BALB/c mice were determined by Fisher's exact test (*P < 0.05, ** P < 0.01).

 
We next examined groups of BALB/c, BALB/c.scid and BALB/c mice depleted of NK cells with anti-asialo-GM₁ antibody. Mice were injected s.c. with 100, 25 or 5 µg of MCA and fibrosarcoma development was monitored for a period of 180 days (Fig. 3B). BALB/c.scid mice and BALB/c mice depleted of NK cells developed sarcomas more frequently than BALB/c control mice regardless of the dose of MCA administered. These data supported those in the C57BL/6 strain indicating that both NK cells and NKT cells contribute to natural host protective immunity in this model.

IL-12 reduces sarcoma incidence and growth rate in a NK cell-dependent fashion
Given that Noguchi et al. (2) previously demonstrated that IL-12 prolonged the latent period for tumor induction by MCA, we next evaluated the incidence and growth rates of sarcoma in the same groups of BALB/c mice (Fig. 3B) treated with IL-12 and 100 µg MCA. Because of the latency of these tumors, and the long period of IL-12 treatment, we could not readily test various IL-12 regimes and therefore employed a similar IL-12 treatment schedule to Noguchi et al. (2) (see Methods). Recombinant mouse IL-12 administered over a 20-week course was shown to significantly (P < 0.05) reduce the incidence of sarcoma in wild-type mice receiving MCA (Fig. 4A). Mice receiving IL-12 appeared healthy and gained weight (data not shown). A reduction in sarcoma incidence was also observed in BALB/c.scid mice receiving IL-12, suggesting that T cells, in particular NKT cells, were not essential for IL-12-mediated anti-tumor activity. By contrast, IL-12 had no effect on sarcoma incidence in mice depleted of NK cells. Individual sarcomas arising in these groups were monitored for growth weekly and their rate of growth was compared with tumors arising in BALB/c mice receiving MCA alone (Fig. 4B). In concert with IL-12-mediated reductions in sarcoma incidence, treatment also significantly reduced sarcoma growth rate. Notably, the suppression of tumor growth was dependent upon NK cells, but not T cells, including NKT cells. Interestingly, IL-12 treatment of NK cell-depleted mice led to an increase in mean tumor growth rate. It may be that the altered cytokine environment induced by IL-12 in the absence of NK cells promotes tumor growth.

View larger version (41K): [in this window] [in a new window]   Fig. 4. IL-12 reduces sarcoma incidence and growth rate in a NK cell-dependent fashion. Similar groups of BALB/c and BALB/c.scid mice injected s.c. in the hind flank with 100 µg MCA were additionally treated with 250 U of mouse IL-12 i.p. 5 days a week for 20 weeks, in a schedule of 3 weeks on and 1 week off. One group of BALB/c mice was also depleted of NK cells (+ anti-asGM1). Sarcoma development was recorded (A) at 180 days as a percentage of the mice in each group (in parentheses). Significant differences from groups of mice not receiving IL-12 were determined by Fisher's exact test (*P < 0.05, ** P < 0.01). (B) Individual tumor growth was measured weekly with a caliper square as the product of two diameters. Growth rates were calculated from individual growth curves and the mean growth rate of each group was compared with BALB/c mice receiving 100 µg MCA alone (standardized to 1.0). The significance of IL-12 treatment was determined by the Mann–Whitney test (*P < 0.05). Innate immune control of MCA-induced sarcoma Innate immune control of MCA-induced sarcoma Innate immune control of MCA-induced sarcoma Innate immune control of MCA-induced sarcoma Innate immune control of MCA-induced sarcoma Innate immune control of MCA-induced sarcoma Innate immune control of MCA-induced sarcoma Innate immune control of MCA-induced sarcoma

 

	Concluding remarks

Top Abstract Introduction Methods Results and discussion Concluding remarks References

 
This study has significantly enhanced our understanding of what effector cells contribute to host immune protection from MCA-induced sarcoma. Previously, and herein, we have illustrated very specifically that NKT cells are critical for host resistance to sarcoma formation. The use of a specific regime of anti-asialo-GM₁ antibody that depletes NK cells, but leaves NKT cells intact, has enabled us to demonstrate that NK cells also are critical for an effective immune reaction to MCA-induced sarcoma. These data compare well with the recent observations that specific activation of CD1d-restricted NKT cells by exogenous stimuli such as IL-12 or -Gal-Cer can result in the potent activation of NK cell cytokine production, proliferation and cytotoxicity (15,20). The activation of NK cell effector functions by NKT cell IFN- production and antigen-presenting cell IL-12 production (20) is also consistent with an important role for endogenous IL-12 (6) and IFN- (Smyth, unpublished data) in host natural immunity to MCA-induced sarcoma.

Clearly IL-12 treatment also suppressed the initiation and growth of MCA-induced sarcomas; however, the anti-tumor activity of IL-12 was not strictly dependent on the presence of V14J281 NKT cells. While the IL-12 treatment experiments further supported an important role for effector NK cells in controlling sarcoma initiation and growth, it must be noted that in other tumor models we have demonstrated that the relative dose of IL-12 administered dictates the relative role of NK and NKT cells (21). NKT cells have higher basal levels of IL-12 receptor expression than NK cells (22) and thus it is probable that at lower doses of IL-12, perhaps more akin to those naturally triggered by MCA-induced tumors, NKT cell function is an important amplifier of an effective anti-tumor response. Recent evidence supports the ability of TCR stimulated NKT cells to rapidly secrete IFN- that promotes secondary activation of NK cell proliferation and effector functions (15). It now remains to be formally demonstrated by adoptive transfer experiments exactly how NKT cells induce NK cell activity against MCA-induced tumors.

Sarcoma is a well-studied experimental tumor in mice, but is relatively infrequent in humans. The use of adoptive transfer experiments and the recent exciting development of CD1d tetramers that can detect NKT cells (23,24), should enable better dissection of how NK cells and NKT cells collaborate to control immune rejection of MCA-induced sarcoma, and whether other highly immunogenic tumors are innately controlled by both NK and NKT cells.

	Acknowledgments

 
M. J. S. is currently supported by a National Health and Medical Research Council of Australia (NH & MRC) Principal Research Fellowship. D. I. G. is supported by the NH & MRC and AdCorp-Diabetes Australia. This work was supported by a NH & MRC Project Grant. We thank the staff of the PMCI animal facility and ARI-BRL for their maintenance and care of the mice in this project.

	Abbreviations

 

MCA methylcholanthrene

pfp perforin

	Notes

 
Transmitting editor: A. Kelso

Received 25 September 2000, accepted 18 December 2000.

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Top Abstract Introduction Methods Results and discussion Concluding remarks References

 

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				J. B. Swann, Y. Hayakawa, N. Zerafa, K. C. F. Sheehan, B. Scott, R. D. Schreiber, P. Hertzog, and M. J. Smyth Type I IFN Contributes to NK Cell Homeostasis, Activation, and Antitumor Function J. Immunol., June 15, 2007; 178(12): 7540 - 7549. [Abstract] [Full Text] [PDF]

				S. E.A. Street, N. Zerafa, M. Iezzi, J. A. Westwood, J. Stagg, P. Musiani, and M. J. Smyth Host Perforin Reduces Tumor Number but Does Not Increase Survival in Oncogene-Driven Mammary Adenocarcinoma Cancer Res., June 1, 2007; 67(11): 5454 - 5460. [Abstract] [Full Text] [PDF]

				J. M. Coquet, K. Kyparissoudis, D. G. Pellicci, G. Besra, S. P. Berzins, M. J. Smyth, and D. I. Godfrey IL-21 Is Produced by NKT Cells and Modulates NKT Cell Activation and Cytokine Production J. Immunol., March 1, 2007; 178(5): 2827 - 2834. [Abstract] [Full Text] [PDF]

				A. V. Gorbachev, H. Kobayashi, D. Kudo, C. S. Tannenbaum, J. H. Finke, S. Shu, J. M. Farber, and R. L. Fairchild CXC Chemokine Ligand 9/Monokine Induced by IFN-{gamma} Production by Tumor Cells Is Critical for T Cell-Mediated Suppression of Cutaneous Tumors J. Immunol., February 15, 2007; 178(4): 2278 - 2286. [Abstract] [Full Text] [PDF]

				J. D. Bui, R. Uppaluri, C.-S. Hsieh, and R. D. Schreiber Comparative Analysis of Regulatory and Effector T Cells in Progressively Growing versus Rejecting Tumors of Similar Origins. Cancer Res., July 15, 2006; 66(14): 7301 - 7309. [Abstract] [Full Text] [PDF]

				M. J. Smyth, Y. Hayakawa, E. Cretney, N. Zerafa, P. Sivakumar, H. Yagita, and K. Takeda IL-21 Enhances Tumor-Specific CTL Induction by Anti-DR5 Antibody Therapy J. Immunol., May 15, 2006; 176(10): 6347 - 6355. [Abstract] [Full Text] [PDF]

				M. J. Smyth, M. W. L. Teng, J. Swann, K. Kyparissoudis, D. I. Godfrey, and Y. Hayakawa CD4+CD25+ T Regulatory Cells Suppress NK Cell-Mediated Immunotherapy of Cancer J. Immunol., February 1, 2006; 176(3): 1582 - 1587. [Abstract] [Full Text] [PDF]

				J. D. Bui, L. N. Carayannopoulos, L. L. Lanier, W. M. Yokoyama, and R. D. Schreiber IFN-Dependent Down-Regulation of the NKG2D Ligand H60 on Tumors J. Immunol., January 15, 2006; 176(2): 905 - 913. [Abstract] [Full Text] [PDF]

				P. Sinha, V. K. Clements, and S. Ostrand-Rosenberg Interleukin-13-regulated M2 Macrophages in Combination with Myeloid Suppressor Cells Block Immune Surveillance against Metastasis Cancer Res., December 15, 2005; 65(24): 11743 - 11751. [Abstract] [Full Text] [PDF]

				M. J. Smyth, J. Swann, E. Cretney, N. Zerafa, W. M. Yokoyama, and Y. Hayakawa NKG2D function protects the host from tumor initiation J. Exp. Med., September 6, 2005; 202(5): 583 - 588. [Abstract] [Full Text] [PDF]

				R. Takaki, Y. Hayakawa, A. Nelson, P. V. Sivakumar, S. Hughes, M. J. Smyth, and L. L. Lanier IL-21 Enhances Tumor Rejection through a NKG2D-Dependent Mechanism J. Immunol., August 15, 2005; 175(4): 2167 - 2173. [Abstract] [Full Text] [PDF]

				H. Nishikawa, T. Kato, I. Tawara, T. Takemitsu, K. Saito, L. Wang, Y. Ikarashi, H. Wakasugi, T. Nakayama, M. Taniguchi, et al. Accelerated chemically induced tumor development mediated by CD4+CD25+ regulatory T cells in wild-type hosts PNAS, June 28, 2005; 102(26): 9253 - 9257. [Abstract] [Full Text] [PDF]

				M. J. Smyth, M. E. Wallace, S. L. Nutt, H. Yagita, D. I. Godfrey, and Y. Hayakawa Sequential activation of NKT cells and NK cells provides effective innate immunotherapy of cancer J. Exp. Med., June 20, 2005; 201(12): 1973 - 1985. [Abstract] [Full Text] [PDF]

				M. S. Duthie and S. J. Kahn NK cell activation and protection occur independently of natural killer T cells during Trypanosoma cruzi infection Int. Immunol., May 1, 2005; 17(5): 607 - 613. [Abstract] [Full Text] [PDF]

				L. S. Metelitsa, H.-W. Wu, H. Wang, Y. Yang, Z. Warsi, S. Asgharzadeh, S. Groshen, S. B. Wilson, and R. C. Seeger Natural Killer T Cells Infiltrate Neuroblastomas Expressing the Chemokine CCL2 J. Exp. Med., May 3, 2004; 199(9): 1213 - 1221. [Abstract] [Full Text] [PDF]

				S. E.A. Street, Y. Hayakawa, Y. Zhan, A. M. Lew, D. MacGregor, A. M. Jamieson, A. Diefenbach, H. Yagita, D. I. Godfrey, and M. J. Smyth Innate Immune Surveillance of Spontaneous B Cell Lymphomas by Natural Killer Cells and {gamma}{delta} T Cells J. Exp. Med., March 15, 2004; 199(6): 879 - 884. [Abstract] [Full Text] [PDF]

				L. M. Esteban, T. Tsoutsman, M. A. Jordan, D. Roach, L. D. Poulton, A. Brooks, O. V. Naidenko, S. Sidobre, D. I. Godfrey, and A. G. Baxter Genetic Control of NKT Cell Numbers Maps to Major Diabetes and Lupus Loci J. Immunol., September 15, 2003; 171(6): 2873 - 2878. [Abstract] [Full Text] [PDF]

				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]

				H.-L. Ma, M. J. Whitters, R. F. Konz, M. Senices, D. A. Young, M. J. Grusby, M. Collins, and K. Dunussi-Joannopoulos IL-21 Activates Both Innate and Adaptive Immunity to Generate Potent Antitumor Responses that Require Perforin but Are Independent of IFN-{gamma} J. Immunol., July 15, 2003; 171(2): 608 - 615. [Abstract] [Full Text] [PDF]

				M. V. Dhodapkar, M. D. Geller, D. H. Chang, K. Shimizu, S.-I. Fujii, K. M. Dhodapkar, and J. Krasovsky A Reversible Defect in Natural Killer T Cell Function Characterizes the Progression of Premalignant to Malignant Multiple Myeloma J. Exp. Med., June 16, 2003; 197(12): 1667 - 1676. [Abstract] [Full Text] [PDF]

				T. J. Stewart, M. J. Smyth, G. J. P. Fernando, I. H. Frazer, and G. R. Leggatt Inhibition of Early Tumor Growth Requires J{alpha}18-positive (Natural Killer T) Cells Cancer Res., June 15, 2003; 63(12): 3058 - 3060. [Abstract] [Full Text] [PDF]

				M. J. Smyth and M. H. Kershaw Discovery of an Innate Cancer Resistance Gene? Mol. Interv., June 1, 2003; 3(4): 186 - 189. [Abstract] [Full Text] [PDF]

				S. L. H. van Dommelen, H. A. Tabarias, M. J. Smyth, and M. A. Degli-Esposti Activation of Natural Killer (NK) T Cells during Murine Cytomegalovirus Infection Enhances the Antiviral Response Mediated by NK Cells J. Virol., February 1, 2003; 77(3): 1877 - 1884. [Abstract] [Full Text] [PDF]

				N. Y. Crowe, M. J. Smyth, and D. I. Godfrey A Critical Role for Natural Killer T Cells in Immunosurveillance of Methylcholanthrene-induced Sarcomas J. Exp. Med., July 1, 2002; 196(1): 119 - 127. [Abstract] [Full Text] [PDF]

				J. M. Kelly, K. Takeda, P. K. Darcy, H. Yagita, and M. J. Smyth A Role for IFN-{gamma} in Primary and Secondary Immunity Generated by NK Cell-Sensitive Tumor-Expressing CD80 In Vivo J. Immunol., May 1, 2002; 168(9): 4472 - 4479. [Abstract] [Full Text] [PDF]

				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]

				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]

				E. Cretney, K. Takeda, H. Yagita, M. Glaccum, J. J. Peschon, and M. J. Smyth Increased Susceptibility to Tumor Initiation and Metastasis in TNF-Related Apoptosis-Inducing Ligand-Deficient Mice J. Immunol., February 1, 2002; 168(3): 1356 - 1361. [Abstract] [Full Text] [PDF]

				K. Takeda, M. J. Smyth, E. Cretney, Y. Hayakawa, N. Kayagaki, H. Yagita, and K. Okumura Critical Role for Tumor Necrosis Factor-related Apoptosis-inducing Ligand in Immune Surveillance Against Tumor Development J. Exp. Med., January 14, 2002; 195(2): 161 - 169. [Abstract] [Full Text] [PDF]

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