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Oncotarget. 2017 Jul 11;8(28):45928-45942. doi: 10.18632/oncotarget.17498.

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

Author information

1
Department of Biochemistry, Osaka Dental University, Hirakata, Osaka 5731121, Japan.
2
Department of Biology, Osaka Dental University, Hirakata, Osaka 5731121, Japan.
3
Department of Oral Science, Graduate School of Dentistry, Kanagawa Dental University, Yokosuka, Kanagawa 2388580, Japan.
4
Department of Laboratory Medicine and Pathology, Center for Immunology, Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.

Abstract

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-12 and IL-18 enhanced effector functions, including the expression of IFN-γ 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 Vγ9Vδ2 T cells. Increased expression of IκBζ, IL-12Rβ2 and IL-18Rα following IL-12 and IL-18 stimulation resulted in sustained activation of STAT4 and NF-κB. The enhanced production of IFN-γ and cytotoxic activity are critical for cancer immunotherapy using Vγ9Vδ2 T cells. Thus, the combined treatment of ex vivo-expanded Vγ9Vδ2 T cells with IL-12 and IL-18 may serve as a new strategy for the therapeutic activation of these cells.

KEYWORDS:

IL-12/IL-18; IκBζ; NF-κB p65; STAT4; γδ T cells

PMID:
28521284
PMCID:
PMC5542238
DOI:
10.18632/oncotarget.17498
[Indexed for MEDLINE]
Free PMC Article

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