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Cytokine-mediated activation of human ex vivo-expanded V?9V?2 T cells.

ABSTRACT: V?9V?2 T cells, the major subset of the human peripheral blood ?? T-cell, respond to microbial infection and stressed cells through the recognition of phosphoantigens. In contrast to the growing knowledge of antigen-mediated activation mechanisms, the antigen-independent and cytokine-mediated activation mechanisms of V?9V?2 T cells are poorly understood. Here, we show that interleukin (IL) -12 and IL-18 synergize to activate human ex vivo-expanded V?9V?2 T cells. V?9V?2 T cells treated with IL-12 and IL-18 enhanced effector functions, including the expression of IFN-? and granzyme B, and cytotoxicity. These enhanced effector responses following IL-12 and IL-18 treatment were associated with homotypic aggregation, enhanced expression of ICAM-1 and decreased expression of the B- and T-lymphocyte attenuator (BTLA), a co-inhibitory receptor. IL-12 and IL-18 also induced the antigen-independent proliferation of V?9V?2 T cells. Increased expression of I?B?, IL-12R?2 and IL-18R? following IL-12 and IL-18 stimulation resulted in sustained activation of STAT4 and NF-?B. The enhanced production of IFN-? and cytotoxic activity are critical for cancer immunotherapy using V?9V?2 T cells. Thus, the combined treatment of ex vivo-expanded V?9V?2 T cells with IL-12 and IL-18 may serve as a new strategy for the therapeutic activation of these cells.

SUBMITTER: Domae E

PROVIDER: S-EPMC5542238 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Cytokine-mediated activation of human ex vivo-expanded Vγ9Vδ2 T cells.

Domae Eisuke E Hirai Yuya Y Ikeo Takashi T Goda Seiji S Shimizu Yoji Y

Oncotarget 20170701 28

Vγ9Vδ2 T cells, the major subset of the human peripheral blood γδ T-cell, respond to microbial infection and stressed cells through the recognition of phosphoantigens. In contrast to the growing knowledge of antigen-mediated activation mechanisms, the antigen-independent and cytokine-mediated activation mechanisms of Vγ9Vδ2 T cells are poorly understood. Here, we show that interleukin (IL) -12 and IL-18 synergize to activate human ex vivo-expanded Vγ9Vδ2 T cells. Vγ9Vδ2 T cells treated with IL-1 ...[more]

PMID: 28521284

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Project description:Introduction:Ex vivo-expanded natural killer (NK) cells are a potential candidate for cancer immunotherapy based on high cytotoxicity against malignant tumor cells. However, a limited understanding of the migration of activated NK cells toward solid tumors is a critical dilemma in the development of effective and adoptive NK cell-based immunotherapy. Methods:Ex vivo-expanded NK cells from healthy donors were stained with near-infrared fluorophores at different concentrations. NK cell proliferation and cytotoxicity were assessed using a WST-8 assay, while the expression levels of surface molecules were analyzed by flow cytometry. To investigate the biodistribution of NK cells in both normal and tumor-bearing NSG mice, NK cells labeled with ESNF13 were subjected to NIR fluorescence imaging using the Mini-FLARE imaging system. Finally, mice were sacrificed and histopathological tests were performed in resected organs. Results:The signal intensity of ESNF-stained NK cells was long-lasting at 72 h using concentrations as low as 0.04 µM. At a low dose range, ESNF13 did not affect NK cell purity, expression levels of surface receptors, or cytotoxic functions against MDA-MB-231 cancer cells. Ex vivo-expanded NK cells labeled with ESNF13 had a 4-h biodistribution in non-tumor-bearing NSG mice that mainly localized to the lungs immediately after injection and then fully migrated to the kidney after 4 h. In an MDA-MB-231 tumor-bearing NSG mice with extensive metastasis in both lungs, the fluorescence signal was dominant in both lungs and steady at 1, 2, and 4 h post-injection. In a early phase of tumor progression, administered NK cell migrated to the lungs and tumor sites within 30 min post-injection, the signal dominated the tumor site after 1 h, and remained steady at 4 h. Conclusion:Optical imaging with NIR fluorophore ESNF13 is a highly sensitive, applicable, and inexpensive method for the real-time tracking of ex vivo-expanded NK cells both in vitro and in vivo. Administered NK cells had different patterns of NK cell distribution and accumulation to the tumor site according to tumor progression in triple-negative breast cancer xenograft models.

Dataset Information

Cytokine-mediated activation of human ex vivo-expanded V?9V?2 T cells.

Publications

Cytokine-mediated activation of human ex vivo-expanded Vγ9Vδ2 T cells.

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