RhoB Mediates Phosphoantigen Recognition by Vγ9Vδ2 T Cell Receptor.
RhoB Mediates Phosphoantigen Recognition by Vγ9Vδ2 T Cell Receptor.
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DOI：
10.1016/j.celrep.2016.04.081
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发表时间：
2016-05-31
期刊：
影响因子：
8.8
通讯作者：
Kuball J
中科院分区：
文献类型：
--
作者：
Sebestyen Z;Scheper W;Vyborova A;Gu S;Rychnavska Z;Schiffler M;Cleven A;Chéneau C;van Noorden M;Peigné CM;Olive D;Lebbink RJ;Oostvogels R;Mutis T;Schuurhuis GJ;Adams EJ;Scotet E;Kuball J
人Vγ 9VS2 T细胞通过感知失调的甲羟戊酸途径的磷酸化中间体的升高水平来响应肿瘤细胞，其通过尚未未知的机制被普遍表达的亲丁酸蛋白A1（BTN3A1）翻译成激活信号。在这里，我们开发了一种无偏倚的全基因组筛选方法，将RhoB鉴定为肿瘤细胞中Vγ9Vδ2 TCR活化的关键介体。我们的结果表明，Vγ 9 V δ2 TCR活化受RhoB的GTT活性及其向BTN3A1的再分布调节。这与直接稳定膜中的BTN3A1的细胞骨架变化以及随后RhoB从BTN3A1解离有关。此外，磷酸化抗原积累诱导BTN3A1的构象变化，使得其胞外结构域可被Vγ 9VS2TCR识别。这些互补事件提供了由内向外信号传导作为Vγ 9VS2TCR识别肿瘤细胞的必要步骤的进一步证据。Sebestyen等人表明，Vγ 9VS2TCR活化受肿瘤细胞中RhoB的GT3活性以及RhoB重新定位于BTN3A1的调节。随后，BTN3A1中磷酸化抗原诱导的构象变化导致其被Vγ 9VS2TCR识别。
Human Vγ9Vδ2 T cells respond to tumour cells by sensing elevated levels of phosphorylated intermediates of the dysregulated mevalonate pathway, which is translated into activating signals by the ubiquitously expressed butyrophilin A1 (BTN3A1) through yet unknown mechanisms. Here, we developed an unbiased, genome-wide screening method that identified RhoB as a critical mediator of Vγ9Vδ2 TCR activation in tumour cells. Our results show that Vγ9Vδ2 TCR activation is modulated by the GTPase activity of RhoB and its redistribution to BTN3A1. This is associated with cytoskeletal changes that directly stabilize BTN3A1 in the membrane, and the subsequent dissociation of RhoB from BTN3A1. Furthermore, phosphoantigen accumulation induces a conformational change in BTN3A1, rendering its extracellular domains recognizable by Vγ9Vδ2TCRs. These complementary events provide further evidence for inside-out signaling as an essential step in the recognition of tumor cells by a Vγ9Vδ2TCR. Sebestyen et al. show that Vγ9Vδ2TCR activation is modulated by the GTPase activity of RhoB in tumour cells, and by the relocalization of RhoB to BTN3A1. Subsequently, a phosphoantigen-induced conformational change in BTN3A1 leads to its recognition by Vγ9Vδ2TCRs.
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