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

Eisuke Domae, Yuya Hirai, Takashi Ikeo, Seiji Goda, Yoji Shimizu

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Vγ9Vδ2 T cells, the major subset of the human peripheral blood γd 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 coinhibitory receptor. IL-12 and IL-18 also induced the antigen-independent proliferation of Vγ9Vδ2 T cells. Increased expression of IκBζ, IL-12Rβ2 and IL-18Ra 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.

Original languageEnglish (US)
Pages (from-to)45928-45942
Number of pages15
Issue number28
StatePublished - 2017

Bibliographical note

Funding Information:
This work was supported by JSPS KAKENHI Grant Numbers JP26861583 (E.Domae), JP26870286 (Y.Hirai).

Publisher Copyright:
© Domae et al.


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


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