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

// Eisuke Domae 1 , Yuya Hirai 2 , Takashi Ikeo 1 , Seiji Goda 3 and Yoji Shimizu 4 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 Correspondence to: Eisuke Domae, email: domae-ei@cc.osaka-dent.ac.jp Keywords: γδ T cells, IL-12/IL-18, IκBζ, STAT4, NF-κB p65 Received: May 20, 2016 Accepted: April 07, 2017 Published: April 28, 2017 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.