scholarly journals Critical Role for Tumor Necrosis Factor–related Apoptosis-inducing Ligand in Immune Surveillance Against Tumor Development

2002 ◽  
Vol 195 (2) ◽  
pp. 161-169 ◽  
Author(s):  
Kazuyoshi Takeda ◽  
Mark J. Smyth ◽  
Erika Cretney ◽  
Yoshihiro Hayakawa ◽  
Nobuhiko Kayagaki ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Nk Cells ◽  
Tumor Necrosis ◽  
Nk Cell ◽  
Critical Role ◽  
Immune Surveillance ◽  
Tumor Development ◽  
Neutralizing Monoclonal Antibody ◽  
Ifn Γ ◽  
Necrosis Factor

Natural killer (NK) cells and interferon (IFN)-γ have been implicated in immune surveillance against tumor development. Here we show that tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) plays a critical role in the NK cell–mediated and IFN-γ–dependent tumor surveillance. Administration of neutralizing monoclonal antibody against TRAIL promoted tumor development in mice subcutaneously inoculated with a chemical carcinogen methylcholanthrene (MCA). This protective effect of TRAIL was at least partly mediated by NK cells and totally dependent on IFN-γ. In the absence of TRAIL, NK cells, or IFN-γ, TRAIL-sensitive sarcomas preferentially emerged in MCA-inoculated mice. Moreover, development of spontaneous tumors in p53+/− mice was also promoted by neutralization of TRAIL. These results indicated a substantial role of TRAIL as an effector molecule that eliminates developing tumors.

scholarly journals Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand (Trail) Contributes to Interferon γ–Dependent Natural Killer Cell Protection from Tumor Metastasis

2001 ◽  
Vol 193 (6) ◽  
pp. 661-670 ◽  
Author(s):  
Mark J. Smyth ◽  
Erika Cretney ◽  
Kazuyoshi Takeda ◽  
Robert H. Wiltrout ◽  
Lisa M. Sedger ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Necrosis ◽  
Nk Cell ◽  
Critical Role ◽  
Trail Expression ◽  
Ifn Γ ◽  
Necrosis Factor

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is expressed by in vitro activated natural killer (NK) cells, but the relevance of this observation to the biological function of NK cells has been unclear. Herein, we have demonstrated the in vivo induction of mouse TRAIL expression on various tissue NK cells and correlated NK cell activation with TRAIL-mediated antimetastatic function in vivo. Expression of TRAIL was only constitutive on a subset of liver NK cells, and innate NK cell control of Renca carcinoma hepatic metastases in the liver was partially TRAIL dependent. Administration of therapeutic doses of interleukin (IL)-12, a powerful inducer of interferon (IFN)-γ production by NK cells and NKT cells, upregulated TRAIL expression on liver, spleen, and lung NK cells, and IL-12 suppressed metastases in both liver and lung in a TRAIL-dependent fashion. By contrast, α-galactosylceramide (α-GalCer), a powerful inducer of NKT cell IFN-γ and IL-4 secretion, suppressed both liver and lung metastases but only stimulated NK cell TRAIL-mediated function in the liver. TRAIL expression was not detected on NK cells from IFN-γ–deficient mice and TRAIL-mediated antimetastatic effects of IL-12 and α-GalCer were strictly IFN-γ dependent. These results indicated that TRAIL induction on NK cells plays a critical role in IFN-γ–mediated antimetastatic effects of IL-12 and α-GalCer.

scholarly journals An Essential Role for Tumor Necrosis Factor in Natural Killer Cell–mediated Tumor Rejection in the Peritoneum

1998 ◽  
Vol 188 (9) ◽  
pp. 1611-1619 ◽  
Author(s):  
Mark J. Smyth ◽  
Janice M. Kelly ◽  
Alan G. Baxter ◽  
Heinrich Körner ◽  
Jonathon D. Sedgwick
Keyword(s):  
Tumor Necrosis Factor ◽  
Nk Cells ◽  
Natural Killer ◽  
Mhc Class I ◽  
Tumor Necrosis ◽  
Nk Cell ◽  
Tumor Rejection ◽  
Class I ◽  
Deficient Mice ◽  
Necrosis Factor

Natural killer (NK) cells are thought to provide the first line of defence against tumors, particularly major histocompatibility complex (MHC) class I− variants. We have confirmed in C57BL/6 (B6) mice lacking perforin that peritoneal growth of MHC class I− RMA-S tumor cells in unprimed mice is controlled by perforin-dependent cytotoxicity mediated by CD3− NK1.1+ cells. Furthermore, we demonstrate that B6 mice lacking tumor necrosis factor (TNF) are also significantly defective in their rejection of RMA-S, despite the fact that RMA-S is insensitive to TNF in vitro and that spleen NK cells from B6 and TNF-deficient mice are equally lytic towards RMA-S. NK cell recruitment into the peritoneum was abrogated in TNF-deficient mice challenged with RMA-S or RM-1, a B6 MHC class I− prostate carcinoma, compared with B6 or perforin-deficient mice. The reduced NK cell migration to the peritoneum of TNF-deficient mice correlated with the defective NK cell response to tumor in these mice. By contrast, a lack of TNF did not affect peptide-specific cytotoxic T lymphocyte–mediated rejection of tumor from the peritoneum of preimmunized mice. Overall, these data show that NK cells delivering perforin are the major effectors of class I− tumor rejection in the peritoneum, and that TNF is specifically critical for their recruitment to the peritoneum.

Human plasmacytoid predendritic cells activate NK cells through glucocorticoid-induced tumor necrosis factor receptor-ligand (GITRL)

Blood ◽  
2006 ◽  
Vol 107 (9) ◽  
pp. 3617-3623 ◽  
Author(s):  
Shino Hanabuchi ◽  
Norihiko Watanabe ◽  
Yi-Hong Wang ◽  
Yui-Hsi Wang ◽  
Tomoki Ito ◽  
...  
Keyword(s):  
Nk Cells ◽  
Tumor Necrosis ◽  
Nk Cell ◽  
Tumor Necrosis Factor Receptor ◽  
Type I ◽  
Cell Cytotoxicity ◽  
Cpg Odn ◽  
Ifn Γ ◽  
Nk Cell Cytotoxicity ◽  
Necrosis Factor

Plasmacytoid dendritic cell precursors (pDCs) are professional type I interferon-producing cells, a critical cell type in regulating innate and adaptive immune responses. By microarray gene expression analysis, we found that pDCs activated by virus or CpG-ODN preferentially express the ligand for the glucocorticoid-induced tumor necrosis factor receptor (GITRL), which was confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) and flow cytometry analysis. Using the same approaches, we found GITR is expressed by activated natural killer (NK) cells and T cells. We show that pDCs activated by CpG-ODN promote NK cell cytotoxicity and interferon (IFN)-γ production through type I IFNs and GITRL. Using a GITRL-transfected cell line, we further demonstrate that GITRL promotes NK cell cytotoxicity and IFN-γ production in synergy with interleukin-2 (IL-2), IFN-α, and NKG2D triggering. We also demonstrated that pDCs localized in close contact to NK cells in T-cell areas of the tonsils, and a subpopulation of the pDCs expressed GITRL. This study reveals a novel function of GITR/GITRL in pDC-mediated coactivation of NK cells.

scholarly journals CAM and NK Cells

2004 ◽  
Vol 1 (1) ◽  
pp. 17-27 ◽  
Author(s):  
Kazuyoshi Takeda ◽  
Ko Okumura
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Critical Role ◽  
Immune Surveillance ◽  
Cell Activity ◽  
Tumor Development ◽  
Point Of View ◽  
Cell Functions ◽  
Ancient Times ◽  
Underlying Mechanisms

It is believed that tumor development, outgrowth and metastasis are under the surveillance of the immune system. Although both innate and acquired immune systems play roles, innate immunity is the spearhead against tumors. Recent studies have revealed the critical role of natural killer (NK) cells in immune surveillance and that NK cell activity is considerably influenced by various agents, such as environmental factors, stress, foods and drugs. Some of these NK cell stimulants have been used in complementary and alternative medicine (CAM) since ancient times. Therefore, the value of CAM should be re-evaluated from this point of view. In this review, we overview the intimate correlation between NK cell functions and CAM agents, and discuss possible underlying mechanisms mediating this. In particular, neuro-immune crosstalk and receptors for CAM agents are the most important and interesting candidates for such mechanisms.

Natural killer cell–dependent apoptosis of peripheral murine hematopoietic progenitor cells in response to Fas cross-linking: involvement of tumor necrosis factor-α

Blood ◽  
2001 ◽  
Vol 97 (10) ◽  
pp. 3069-3074 ◽  
Author(s):  
Géraldine Moreau ◽  
Maria Leite-de-Moraes ◽  
Sophie Ezine ◽  
James P. Di Santo ◽  
Michel Dy ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Cross Linking ◽  
Tnf Α ◽  
Ifn Γ ◽  
Factor Α ◽  
Necrosis Factor

Abstract Recently, a marked extramedullary myelopoiesis in Fas/CD95- or FasL/CD95L-deficient mice has been reported. In the present in vitro study, the mechanisms underlying Fas-induced apoptosis of normal peripheral colony-forming unit-C (CFU-C) progenitors in the spleen were analyzed. Surprisingly, it was found that clonogenic progenitors were protected from γIFN plus Fas-induced programmed cell death when Lin+ cells were removed from cultured splenocytes. The cells that rendered CFU-C sensitive to the activation of the Fas pathway did not belong to the T or the myelocytic–monocytic lineage but comprised a non–B-cell subset expressing the activation marker B220. Among CD19− B220+ splenocytes, nearly half were natural killer (NK) 1.1+ cells whose in vivo depletion or deficiency in RAG2-γc−/− mice abrogated the effect of Fas cross-linking. NK cells exerted their accessory function, at least in part, through tumor necrosis factor–α (TNF-α), which they readily produced during pretreatment with the anti-Fas/CD95 monoclonal antibody and IFN-γ and whose addition could compensate for the loss of sensitivity. In conclusion, this study provides evidence that peripheral clonogenic progenitors are not directly responsive to Fas cross-linking, even in the presence of IFN-γ, but require NK cells as a source of TNF-α to make them susceptible to this death pathway.

Involvement of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand in NK Cell-Mediated and IFN-γ-Dependent Suppression of Subcutaneous Tumor Growth

2001 ◽  
Vol 214 (2) ◽  
pp. 194-200 ◽  
Author(s):  
Kazuyoshi Takeda ◽  
Mark J. Smyth ◽  
Erika Cretney ◽  
Yoshihiro Hayakawa ◽  
Noriko Yamaguchi ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Growth ◽  
Tumor Necrosis ◽  
Nk Cell ◽  
Subcutaneous Tumor ◽  
Ifn Γ ◽  
Necrosis Factor

Activation of natural killer cells inhibits liver regeneration in toxin-induced liver injury model in mice via a tumor necrosis factor-α-dependent mechanism

2010 ◽  
Vol 299 (1) ◽  
pp. G275-G282 ◽  
Author(s):  
Hairong Wei ◽  
Haiming Wei ◽  
Hua Wang ◽  
Zhigang Tian ◽  
Rui Sun
Keyword(s):  
Liver Injury ◽  
Liver Regeneration ◽  
Nk Cells ◽  
Tumor Necrosis ◽  
Nk Cell ◽  
Poly I:C ◽  
Injury Model ◽  
Tnf Α ◽  
Ifn Γ ◽  
Necrosis Factor

Liver lymphocytes are enriched in natural killer (NK) cells, and activation of NK cells by injection of polyinosinic-polycytidylic acid (poly I:C) inhibits liver regeneration in the partial hepatectomy model via production of IFN-γ. However, the role of NK cells in liver regeneration in a model of carbon tetrachloride (CCl4)-induced liver injury remains unknown. In this study, we investigated the effect of activation of NK cells induced by poly I:C on liver regeneration in the CCl4 model. Administration of poly I:C suppressed liver regeneration in CCl4-treated mice. Depletion of NK cells but not Kupffer cells or T cells restored liver regeneration in poly I:C/CCl4-treated mice. Poly I:C and CCl4 cotreatment synergistically induced accumulation of NK cells in the liver and NK cell production of IFN-γ and tumor necrosis factor (TNF)-α. Serum levels of these two cytokines were also synergistically induced after poly I:C and CCl4 treatment. Finally, blockage of TNF-α but not IFN-γ restored liver regeneration in poly I:C/CCl4-treated mice. Taken together, these findings suggest that poly I:C treatment inhibits liver regeneration in the CCl4-induced liver injury model via induction of NK cell production of TNF-α.

NK-dependent DC maturation is mediated by TNFα and IFNγ released upon engagement of the NKp30 triggering receptor

Blood ◽  
2005 ◽  
Vol 106 (2) ◽  
pp. 566-571 ◽  
Author(s):  
Massimo Vitale ◽  
Mariella Della Chiesa ◽  
Simona Carlomagno ◽  
Daniela Pende ◽  
Maurizio Aricò ◽  
...  
Keyword(s):  
Nk Cells ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Nk Cell ◽  
Interferon Γ ◽  
Cell Functions ◽  
Relevant Role ◽  
Factor Α ◽  
Necrosis Factor ◽  
Dc Maturation

Abstract Natural killer (NK) cells were recently shown to play a relevant role in the process of dendritic cell (DC) maturation. This function is exerted either by direct DC stimulation or through killing those DCs that did not properly acquire a mature phenotype. While killing of immature DCs is dependent on the function of the NKp30 triggering receptor, the mechanism by which NK cells induce DC maturation is still unclear. In this study, we show that also the NK-mediated induction of DC maturation is dependent on NKp30. Upon NK/DC interaction, resulting in NKp30 engagement, NK cells produced tumor necrosis factor α (TNFα) (and interferon γ [IFNγ]) that, in turn, promoted DC maturation. Masking of NKp30 with specific monoclonal antibodies (mAbs) strongly reduced maturation of DCs cocultured with NK cells. In addition, supernatant from NK cells stimulated via NKp30 induced DC maturation, and this effect was neutralized by anti-TNFα antibodies (Abs). This NKp30 function is controlled by the HLA-specific inhibitory NK receptors. Accordingly, the ability to promote maturation was essentially confined to NK cells expressing the killer immunoglobulin-like receptor–negative (KIR–) NKG2Adull phenotype. Finally, the analysis of perforin-deficient NK cells allowed the dissection of the 2 NKp30-mediated NK-cell functions, since NKp30 could induce cytokine-dependent DC maturation in the absence of NK-mediated DC killing.

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