Domae Eisuke, Hirai Yuya, Ikeo Takashi, Goda Seiji, Shimizu Yoji
Department of Biochemistry, Osaka Dental University, Hirakata, Osaka 5731121, Japan.
Department of Biology, Osaka Dental University, Hirakata, Osaka 5731121, Japan.
Oncotarget. 2017 Jul 11;8(28):45928-45942. doi: 10.18632/oncotarget.17498.
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.
Vγ9Vδ2 T细胞是人类外周血γδ T细胞的主要亚群，通过识别磷酸抗原来响应微生物感染和应激细胞。与对抗原介导的激活机制的认识不断增加形成对比的是，人们对Vγ9Vδ2 T细胞的抗原非依赖性和细胞因子介导的激活机制了解甚少。在这里，我们表明白细胞介素（IL）-12和IL-18协同激活体外扩增的人Vγ9Vδ2 T细胞。用IL-12和IL-18处理的Vγ9Vδ2 T细胞增强了效应功能，包括IFN-γ和颗粒酶B的表达以及细胞毒性。IL-12和IL-18处理后这些增强的效应反应与同型聚集、ICAM-1表达增加和共抑制受体B和T淋巴细胞衰减器（BTLA）表达降低有关。IL-12和IL-18还诱导了Vγ9Vδ2 T细胞的抗原非依赖性增殖。IL-12和IL-18刺激后IκBζ、IL-12Rβ2和IL-18Rα表达增加导致STAT4和NF-κB的持续激活。IFN-γ产生的增加和细胞毒性活性对于使用Vγ9Vδ2 T细胞的癌症免疫治疗至关重要。因此，用IL-12和IL-18联合处理体外扩增的Vγ9Vδ2 T细胞可能作为这些细胞治疗性激活的新策略。
