Highly active microbial phosphoantigen induces rapid yet sustained MEK/Erk- and PI-3K/Akt-mediated signal transduction in anti-tumor human gammadelta T-cells.
Highly active microbial phosphoantigen induces rapid yet sustained MEK/Erk- and PI-3K/Akt-mediated signal transduction in anti-tumor human gammadelta T-cells.
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DOI：
10.1371/journal.pone.0005657
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发表时间：
2009-05-21
期刊：
影响因子：
3.7
通讯作者：
Silva-Santos B
中科院分区：
文献类型：
--
作者：
Correia DV;d'Orey F;Cardoso BA;Lança T;Grosso AR;deBarros A;Martins LR;Barata JT;Silva-Santos B
Vγ9Vδ2 T细胞是人类外周血中主要的γδ亚群，其对非肽性戊烯焦磷酸抗原的独特反应性构成了当前基于γδT细胞的癌症免疫治疗策略的基础。然而，磷抗原介导的人γδT细胞活化的分子机制尚不清楚。特别是，以前的报道描述了异戊烯基焦磷酸和溴代醇焦磷酸激活T细胞受体(TCR)相关信号转导通路的动力学非常缓慢，似乎与这些抗原与Vγ9Vδ2TCR的直接结合不相容。在这里，我们研究了由真细菌和原生动物产生的最有效的天然磷抗原--(E)-4-羟基-3-甲基-2-烯基焦磷酸(HMB-PP)，并检测了它的γδT细胞活化和抗肿瘤特性。我们进行了HMB-PP和抗CD3TCR3单抗OKT3TCR信号的参考诱导剂的比较研究，并跟踪了多个细胞和分子εT细胞激活事件。在Vγ9+T细胞中，hMB-PP激活MEK/ERK和PI-3K/AKT途径的速度与OKT3一样快，并诱导了几乎相同的转录谱。此外，MEK/ERK和PI-3K/AKT活性在hMB-PP的T细胞活化、增殖和抗肿瘤细胞毒作用中是必不可少的，抗体阻断V-γδ9+γ后，这些活性也被取消。令人惊讶的是，hMB-PP处理不会引起表面TCR水平的下调，从而在再次刺激时维持γδT细胞的激活。这最终在体外和体内都转化为强大的人γδT细胞抗肿瘤功能。当将人白血病细胞移植到淋巴细胞缺乏的小鼠中时，有效的癌症免疫治疗策略的开发关键取决于我们最大化抗肿瘤效应T细胞反应的能力。通过表征HMB-PP介导的高细胞毒性Vγ9+T细胞亚群激活的细胞内机制，我们的数据有力地支持了这种微生物抗原在新的癌症临床试验中的使用。
The unique responsiveness of Vγ9Vδ2 T-cells, the major γδ subset of human peripheral blood, to non-peptidic prenyl pyrophosphate antigens constitutes the basis of current γδ T-cell-based cancer immunotherapy strategies. However, the molecular mechanisms responsible for phosphoantigen-mediated activation of human γδ T-cells remain unclear. In particular, previous reports have described a very slow kinetics of activation of T-cell receptor (TCR)-associated signal transduction pathways by isopentenyl pyrophosphate and bromohydrin pyrophosphate, seemingly incompatible with direct binding of these antigens to the Vγ9Vδ2 TCR. Here we have studied the most potent natural phosphoantigen yet identified, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), produced by Eubacteria and Protozoa, and examined its γδ T-cell activation and anti-tumor properties. We have performed a comparative study between HMB-PP and the anti-CD3ε monoclonal antibody OKT3, used as a reference inducer of bona fide TCR signaling, and followed multiple cellular and molecular γδ T-cell activation events. We show that HMB-PP activates MEK/Erk and PI-3K/Akt pathways as rapidly as OKT3, and induces an almost identical transcriptional profile in Vγ9+ T-cells. Moreover, MEK/Erk and PI-3K/Akt activities are indispensable for the cellular effects of HMB-PP, including γδ T-cell activation, proliferation and anti-tumor cytotoxicity, which are also abolished upon antibody blockade of the Vγ9+ TCR Surprisingly, HMB-PP treatment does not induce down-modulation of surface TCR levels, and thereby sustains γδ T-cell activation upon re-stimulation. This ultimately translates in potent human γδ T-cell anti-tumor function both in vitro and in vivo upon transplantation of human leukemia cells into lymphopenic mice, The development of efficient cancer immunotherapy strategies critically depends on our capacity to maximize anti-tumor effector T-cell responses. By characterizing the intracellular mechanisms of HMB-PP-mediated activation of the highly cytotoxic Vγ9+ T-cell subset, our data strongly support the usage of this microbial antigen in novel cancer clinical trials.
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影响因子：
11.2
作者：
Dieli F;Vermijlen D;Fulfaro F;Caccamo N;Meraviglia S;Cicero G;Roberts A;Buccheri S;D'Asaro M;Gebbia N;Salerno A;Eberl M;Hayday AC
通讯作者：
Hayday AC
影响因子：
4.4
作者：
Ali, Zahida;Shao, Lingyan;Chen, Zheng W.
通讯作者：
Chen, Zheng W.
影响因子：
20.3
作者：
Chen, Yong;Shao, Lingyun;Chen, Zheng W.
通讯作者：
Chen, Zheng W.
影响因子：
4.4
作者：
Kabelitz, D;Wesch, D;Zöller, M
通讯作者：
Zöller, M
影响因子：
4.4
作者：
Corvaisier, M;Moreau-Aubry, A;Jotereau, F
通讯作者：
Jotereau, F