Flagellin increases death receptor-mediated cell death in a RIP1-dependent manner
Flagellin increases death receptor-mediated cell death in a RIP1-dependent manner
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DOI：
10.1016/j.imlet.2017.11.007
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发表时间：
2018-01-01
影响因子：
4.4
通讯作者：
Koncz, Gabor
中科院分区：
文献类型：
--
作者：
Hancz, Dora;Szabo, Aniko;Koncz, Gabor
有效的佐剂具有同时触发先天性和适应性免疫应答的潜力。鞭毛蛋白是一种独特的病原体来源的蛋白质，其被模式识别受体（PRR）以及B细胞和T细胞受体识别，从而在先天免疫和适应性免疫之间提供重要的联系。上述性质将鞭毛蛋白定义为最佳佐剂。免疫原性细胞死亡的诱导可能是癌症免疫治疗背景下佐剂的另一个期望，因为它们能够通过吞噬垂死细胞激活树突状细胞（DC）以呈递肿瘤抗原。鞭毛蛋白在DC和淋巴细胞活化过程中的免疫刺激潜力已被充分证明，但其确切机制尚未完全探讨。基于这一局限性，我们试图研究鞭毛蛋白对各种细胞死亡过程的潜在调节作用，因为我们知道鞭毛蛋白在调节各种类型的免疫应答的最终结果中起着有害的作用。并伴随以TLR 5依赖性方式增加植物血凝素激活的T淋巴细胞的细胞毒性潜力。与这些鞭毛蛋白介导的对死亡受体诱导的信号传导事件的影响相反，线粒体凋亡途径保持不受影响。此外，野生型沙门氏菌的细胞培养物上清液，但不是其鞭毛蛋白缺陷的变体，能够增强Fas诱导的细胞死亡过程。为了确定鞭毛蛋白介导的细胞死亡水平升高的分子机制，我们能够检测RIP1依赖性信号事件的上调。这些发现表明，模式识别和不同的死亡受体的协同作用能够启动细胞死亡过程的RIP依赖的细胞死亡模式的动员。这一发现突出了鞭毛蛋白作为与肿瘤免疫治疗相关的潜在佐剂的能力。
Efficient adjuvants have the potential to trigger both innate and adaptive immune responses simultaneously. Flagellin is a unique pathogen-derived protein, which is recognized by pattern recognition receptors (PRRs) as well as by B-cell and T cell receptors thus providing an important link between innate and adaptive immunity. The aforementioned properties define flagellin as an optimal adjuvant. The induction of immunogenic cell death could be an additional expectation for adjuvants in the context of cancer immunotherapy due to their ability to activate dendritic cells (DC) to present tumor antigens through the engulfment of dying cells. The immunostimulatory potential of flagellin in the course of DC and lymphocyte activation is well documented, however the exact mechanism is not fully explored. Based on this limitation we sought to investigate the potential modulatory effects of flagellin on various cell death processes knowing that it plays detrimental roles in regulating the final outcome of various types of immune responses.Here we provide evidence that the pre-treatment of Jurkat T-cells with recombinant flagellin is able to increase the degree of cell death provoked by FasL or TNF-alpha, and concomitantly increases the cytotoxic potential of phytohemagglutinin activated T-lymphocytes in a TLR5 dependent way. In contrast to these flagellin-mediated effects on the death receptor-induced signaling events, the mitochondrial apoptotic pathway remained unaffected. Furthermore, the cell culture supernatant of wild type Salmonella enteritidis bacteria, but not their flagellin deficient variant, was able to enhance the Fas-induced cell death process. To define the molecular mechanisms of flagellin-mediated elevated levels of cell death we were able to detect the upregulation of RIP1-dependent signaling events. These findings demonstrate that the cooperative actions of pattern recognition and different death receptors are able to initiate the cell death process with the mobilization of RIP-dependent cell death modalities. This finding highlights the capability of flagellin to act as a potential adjuvant which is relevant for tumor immunotherapy.