Stress-related and homeostatic cytokines regulate Vγ9Vδ2 T-cell surveillance of mevalonate metabolism
Stress-related and homeostatic cytokines regulate Vγ9Vδ2 T-cell surveillance of mevalonate metabolism
复制标题
DOI：
10.4161/21624011.2014.953410
复制
发表时间：
2014-08-01
期刊：
影响因子：
7.2
通讯作者：
Thurnher, Martin
中科院分区：
文献类型：
--
作者：
Gruenbacher, Georg;Nussbaumer, Oliver;Thurnher, Martin
潜在致癌的甲羟戊酸途径为蛋白质预烯基化提供了基石，并诱导细胞增殖，因此是一个重要的治疗靶点。在甲氧戊酸代谢产物中，只有焦磷酸异戊烯(IPP)被认为是灵长类动物特有的、具有抗肿瘤潜力的先天类V-Gamma 9V Delta 2T细胞的免疫相关抗原。我们在这里表明，用应激相关的、炎症体依赖的细胞因子白介素18(IL-18)预处理的V-Gamma 9V Delta 2T细胞不仅可以被IPP激活，而且可以被所有下游的异戊二烯焦磷酸激活，这些焦磷酸表现出抗原和细胞-外源性代谢信号的组合特征。以这种方式诱导的V-Gamma 9V Delta 2 T细胞即使在严重的淋巴细胞减少条件下也能有效地增殖，抗氧化剂N-乙酰半胱氨酸显著促进以中枢记忆表型为主的Gamma Delta T细胞的重建。动态平衡细胞因子IL-15以非抗原依赖的方式诱导效应细胞分化，在抗原再次相遇时迅速产生丰富的干扰素-γ。IL-15诱导的效应型γ-增量T细胞表达细胞毒性淋巴细胞相关蛋白CD56、CD96、CD161和穿孔素。在异戊二烯类焦磷酸的刺激下，这些效应细胞上调CD107a的表面表达，并在体外对肿瘤细胞表现出强大的细胞毒作用。我们的数据阐明了对先天免疫监控机制的理解，并将有助于有效的癌症免疫治疗控制产生强大的V-Gamma 9V Delta 2T细胞亚群。
The potentially oncogenic mevalonate pathway provides building blocks for protein prenylation and induces cell proliferation and as such is an important therapeutic target. Among mevalonate metabolites, only isopentenyl pyrophosphate (IPP) has been considered to be an immunologically relevant antigen for primate-specific, innate-like V gamma 9V delta 2 T cells with antitumor potential. We show here that V gamma 9V delta 2 T cells pretreated with the stress-related, inflammasome-dependent cytokine interleukin 18 (IL-18) were potently activated not only by IPP but also by all downstream isoprenoid pyrophosphates that exhibit combined features of antigens and cell-extrinsic metabolic cues. V gamma 9V delta 2 T cells induced this way effectively proliferated even under severe lymphopenic conditions and the antioxidant N-acetylcysteine significantly improved reconstitution of gamma delta T cells predominantly with a central memory phenotype. The homeostatic cytokine IL-15 induced the differentiation of effector cells in an antigen-independent fashion, which rapidly produced abundant interferon gamma (IFN gamma) upon antigen re-encounter. IL-15 induced effector gamma delta T cells displayed increased levels of the cytotoxic lymphocyte-associated proteins CD56, CD96, CD161 and perforin. In response to stimulation with isoprenoid pyrophosphates, these effector cells upregulated surface expression of CD107a and exhibited strong cytotoxicity against tumor cells in vitro. Our data clarify understanding of innate immunosurveillance mechanisms and will facilitate the controlled generation of robust V gamma 9V delta 2 T cell subsets for effective cancer immunotherapy.