Human umbilical cord blood NK T cells kill tumors by multiple cytotoxic mechanisms

Balgansuren, Gansuvd; Hagihara, Masao; Yu, Ying; Inoue, H.; Ueda, Yôko; Tsuchiya, Takahide; Masui, Aya; Ando, Kiyoshi; Nakamura, Yoshihiko; Munkhtuvshin, Namid; Kato, Shingo; Thomas, Judith M.; Hotta, Tomomitsu

doi:10.1016/s0198-8859(01)00382-2

Cited by 31 publications

(23 citation statements)

References 40 publications

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“…Following activation with PMA and ionomycin, CD69 and CD40L expression were up-regulated, but other activation and costimulatory molecules, particularly CD25 (IL-2R␣), CD122 (IL-2R␤), and CD28, remained negative. Regardless of weekly stimulation with ␣-GalCer-pulsed DC in the presence of rhIL-2 and rhIL-15, the growth of rhesus NKT cells was slow, compared with that of human V␣24 ϩ neonatal cord blood NKT cells (46). In addition, rhesus NKT cells consistently failed to produce intracellular IL-2 following stimulation with PMA and ionomycin.…”

Section: Discussionmentioning

confidence: 97%

Phenotypic and Functional Characterization of Long-Term Cultured Rhesus Macaque Spleen-Derived NKT Cells

Balgansuren

Hubbard

Hutchings

et al. 2003

The Journal of Immunology

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Natural killer T cells are immunoregulatory cells, which have important roles in tolerance and autoimmunity, as demonstrated primarily in mice and humans. In this study, we define the phenotype and function of Vα24+ T cells derived from the spleens of rhesus macaques, a species increasingly used in models of immune tolerance. Vα24+ cells were isolated and expanded with monocyte-derived immature dendritic cells in the presence of α-galactosylceramide, IL-2, and IL-15. Rhesus NKT cells were stained with mAbs against both Vα24 and the invariant complementarity-determining region 3 epitope of the human Vα24/JαQ TCR. The cells were CD4, CD8 double negative and expressed CD56. Rhesus NKT cells also exhibited moderate to high expression of CD95, CD45RO, CD11a, and β7 integrin, but did not express CD45 RA, CD62L, CCR7, CD28, and other activation, costimulatory molecules (CD69 and CD40L). By intracellular staining, >90% of unstimulated rhesus NKT cells expressed IL-10, but not IFN-γ. However, the latter was strongly expressed after stimulation. Rhesus NKT secreted large amounts of TGF-β, IL-13, and IL-6, and modest levels of IFN-γ, whereas IL-10 secretion was negligible and no detectable IL-4 was observed either intracellularly or in culture supernatants. Functionally, the NKT cells and their supernatants suppressed T cell proliferation in allogeneic MLR. We conclude that long-term cultured rhesus macaque spleen-derived Vα24+ T cells are semi-invariant double-negative cells with effector memory phenotype. These cells are semianergic, polarized to a uniquely Th3 > T regulatory-1 regulatory cell phenotype, and have regulatory/suppressive function in vitro.

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Section: Discussionmentioning

confidence: 97%

Phenotypic and Functional Characterization of Long-Term Cultured Rhesus Macaque Spleen-Derived NKT Cells

Balgansuren

Hubbard

Hutchings

et al. 2003

The Journal of Immunology

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“…NKT cells have become a major focus for those who study the innate immune response to tumors and infectious disease. 2 Several malignant human hematopoietic cell types express CD1d on their surface, 18,19 but the overall role of CD1d in antitumor immunity is not well understood. We have previously demonstrated that hematopoietic tumors like the murine T-cell lymphoma (L5178Y-R) shed glycolipids that mask CD1d-mediated antigen presentation to NKT cells.…”

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Inhibition of antitumor immunity by invariant natural killer T cells in a T‐cell lymphoma model in vivo

Renukaradhya

Sriram

et al. 2006

Intl Journal of Cancer

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We have investigated the role of the host's CD1d-dependent innate antitumor immune response in a murine T-cell lymphoma model in vivo. We found that C57BL/6 wildtype (WT) mice inoculated with RMA/S cells transfected with murine CD1d1 died at the same rate as mice inoculated with vector-transfected cells. In contrast, natural killer T (NKT) cell-deficient CD1d or Ja18 knockout mice inoculated with CD1d-transfected RMA/S cells survived significantly longer than mice inoculated with vector-transfected RMA/S cells, implicating the involvement of invariant NKT (iNKT) cells in inhibiting antitumor activity in vivo. In contrast to the mutant mice, which produced more of the proinflammatory cytokines IFN-c and GM-CSF, WT mice produced significantly elevated amounts of IL-13. Antitumor activity in the knockout mice was not due to the development of CD1d-specific cytotoxic T lymphocytes or circulating antibodies. However, iNKT cell numbers were elevated in tumor-bearing mice. Thus, iNKT cells may be playing a negative role in the host's antitumor immune response against T-cell lymphomas in a CD1d-dependent manner. ' 2006 Wiley-Liss, Inc.Key words: T-cell lymphoma; RMA/S; invariant NKT cells; CD1d molecules; cytokines Despite apparent immunocompetence in the host, lymphomas can arise nonetheless, evading the body's attempts at tumor immunosurveillance. Following transformation, the host's innate immune response is essential in controlling the dissemination and growth of metastatic disease. Immunosurveillance against spontaneously occurring lymphomas is not well understood. Understanding the molecular mechanisms that regulate divergent arms of the immune response is a key to develop effective immunotherapies for many diseases, including cancer.1 Recent studies have suggested an immunosurveillance function for a unique subpopulation of T cells that play an important role in innate immunity called natural killer T (NKT) cells.2 NKT cells are defined as T cells expressing markers on the surface shared with NK cells, and that rapidly secrete both Th1 and Th2 cytokines upon T-cell receptor (TCR) ligation. 3,4 Rather than recognizing peptides presented by MHC class I or class II molecules, NKT cells recognize lipid antigens presented by the MHC class I-like CD1d molecule.5 NKT cells are key players in the regulation of antitumor immunity, particularly in experimental models of tumor immunotherapy, including IL-12 or a-galactosylceramide (a-GalCer) administration.6 In a mouse model in which tumors spontaneously regress after initial growth and then recur, the negative regulation of tumor immunosurveillance by IL-13, possibly produced by CD41 NKT cells, has been reported. 7,8 In a more recent study, the same group has shown that a reduction in pulmonary metastases in the CT26 nonregressor colon carcinoma model occurs following the elimination of CD4 1 NKT cells, further illustrating an inhibitory role for NKT cells in antitumor immunity. 9 To date, the role of invariant (Va14Ja18 1 ) NKT (iNKT) cells in the evasion of hematopoieti...

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“…Although our studies show that NKT cells use perforin and granzyme B to mediate caspase 3-dependent apoptosis in atherosclerotic lesions, other studies report that NKT cells can use multiple mechanisms to mediate cytotoxicity. Thus, NKT cell cytotoxicity directed against tumors used perforin, 15,16,30 tumor necrosis factor, or the combination of perforin, tumor necrosis factor, and Fas ligand (CD95L), 63 or TRAIL (TNF-related apoptosisinducing ligand). 64 Our finding that perforin −/− NKT cell transfer is associated with reduced TUNEL-positive apoptotic cells and active caspase 3-positive cells in atherosclerotic lesions is consistent with previous reports that perforin-dependent granzyme B's action initiates caspase 3-dependent apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Macrophages, including macrophage-derived foam cells, express CD1d in atherosclerotic lesions 70 and NKT cells selectively target CD1d-expressing cells for killing primarily via perforin/granzyme B mechanisms. 29,71 Because vascular smooth muscle cells associated with lesions do not express CD1d, 70 these cells are likely to be spared. This suggestion is consistent with our previous observation that vascular smooth muscle cell numbers associated with lesions are unaffected by NKT cells.…”

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CD4 ⁺ Natural Killer T Cells Potently Augment Aortic Root Atherosclerosis by Perforin- and Granzyme B-Dependent Cytotoxicity

Kanellakis

et al. 2015

Circulation Research

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Human umbilical cord blood NK T cells kill tumors by multiple cytotoxic mechanisms

Cited by 31 publications

References 40 publications

Phenotypic and Functional Characterization of Long-Term Cultured Rhesus Macaque Spleen-Derived NKT Cells

Phenotypic and Functional Characterization of Long-Term Cultured Rhesus Macaque Spleen-Derived NKT Cells

Inhibition of antitumor immunity by invariant natural killer T cells in a T‐cell lymphoma model in vivo

CD4 ⁺ Natural Killer T Cells Potently Augment Aortic Root Atherosclerosis by Perforin- and Granzyme B-Dependent Cytotoxicity

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Human umbilical cord blood NK T cells kill tumors by multiple cytotoxic mechanisms

Cited by 31 publications

References 40 publications

Phenotypic and Functional Characterization of Long-Term Cultured Rhesus Macaque Spleen-Derived NKT Cells

Phenotypic and Functional Characterization of Long-Term Cultured Rhesus Macaque Spleen-Derived NKT Cells

Inhibition of antitumor immunity by invariant natural killer T cells in a T‐cell lymphoma model in vivo

CD4 + Natural Killer T Cells Potently Augment Aortic Root Atherosclerosis by Perforin- and Granzyme B-Dependent Cytotoxicity

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CD4 ⁺ Natural Killer T Cells Potently Augment Aortic Root Atherosclerosis by Perforin- and Granzyme B-Dependent Cytotoxicity