Thermal- and oxidative stress causes enhanced release of NKG2D ligand-bearing immunosuppressive exosomes in leukemia/lymphoma T and B cells.
Thermal- and oxidative stress causes enhanced release of NKG2D ligand-bearing immunosuppressive exosomes in leukemia/lymphoma T and B cells.
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DOI：
10.1371/journal.pone.0016899
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发表时间：
2011-02-25
期刊：
影响因子：
3.7
通讯作者：
Mincheva-Nilsson L
中科院分区：
文献类型：
--
作者：
Hedlund M;Nagaeva O;Kargl D;Baranov V;Mincheva-Nilsson L
免疫逃避与NK细胞功能不足有关的免疫逃避被认为是许多血液恶性肿瘤的高复发率和致命性后果的原因。在本报告中，我们使用Jurkat和Raji细胞系作为研究T细胞和B细胞白血病/淋巴瘤中NKG2D受体-配体系统的模型。应用实时定量RT-PCR和免疫流式细胞术，我们发现Jurkat和Raji细胞结构性地表达应激诱导的NKG2D配体MICA/B和ULBP1和2的mRNA和蛋白，并以细胞系特异性和应激特异性的方式上调表达。此外，我们通过电子显微镜、免疫流式细胞仪和免疫印迹检测发现，这些配体在外体、内体来源的纳米级微囊上表达和分泌。NKG2D配体外切体作为诱饵，在体外下调NKG2D受体介导的细胞毒作用，从而损害NK细胞的功能。有趣的是，热应激和氧化应激增加了外体分泌，产生了更多的可溶性NKG2D配体，从而加剧了细胞毒性反应的损害。综上所述，我们的结果可能部分解释了临床上观察到的白血病/淋巴瘤患者的NK细胞功能障碍。在设计细胞抑制和高温抗癌治疗时，应考虑热应激和氧化应激的不利影响，促进免疫抑制外切体的释放。
Immune evasion from NK surveillance related to inadequate NK-cell function has been suggested as an explanation of the high incidence of relapse and fatal outcome of many blood malignancies. In this report we have used Jurkat and Raji cell lines as a model for studies of the NKG2D receptor-ligand system in T-and B cell leukemia/lymphoma. Using real-time quantitative RT-PCR and immunoflow cytometry we show that Jurkat and Raji cells constitutively express mRNA and protein for the stress-inducible NKG2D ligands MICA/B and ULBP1 and 2, and up-regulate the expression in a cell-line specific and stress-specific manner. Furthermore, we revealed by electron microscopy, immunoflow cytometry and western blot that these ligands were expressed and secreted on exosomes, nanometer-sized microvesicles of endosomal origin. Acting as a decoy, the NKG2D ligand-bearing exosomes downregulate the in vitro NKG2D receptor-mediated cytotoxicity and thus impair NK-cell function. Interestingly, thermal and oxidative stress enhanced the exosome secretion generating more soluble NKG2D ligands that aggravated the impairment of the cytotoxic response. Taken together, our results might partly explain the clinically observed NK-cell dysfunction in patients suffering from leukemia/lymphoma. The adverse effect of thermal and oxidative stress, enhancing the release of immunosuppressive exosomes, should be considered when cytostatic and hyperthermal anti-cancer therapies are designed.
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DOI：
10.1073/pnas.201238598
发表时间：
2001-09-25
影响因子：
11.1
作者：
Cerwenka, A;Baron, JL;Lanier, LL
通讯作者：
Lanier, LL
影响因子：
20.3
作者：
Salih, HR;Antropius, H;Steinle, A
通讯作者：
Steinle, A
影响因子：
11.2
作者：
Hayashi, T;Imai, K;Nakachi, K
通讯作者：
Nakachi, K
影响因子：
2.3
作者：
Clayton, A;Tabi, Z
通讯作者：
Tabi, Z
影响因子：
4.4
作者：
Hedlund, Malin;Stenqvist, Ann-Christin;Mincheva-Nilsson, Lucia
通讯作者：
Mincheva-Nilsson, Lucia