Natural killer cell cytotoxicity is suppressed by exposure to the human NKG2D ligand MICA*008 that is shed by tumor cells in exosomes.
Natural killer cell cytotoxicity is suppressed by exposure to the human NKG2D ligand MICA*008 that is shed by tumor cells in exosomes.
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DOI：
10.1158/0008-5472.can-09-1688
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发表时间：
2010-01-15
期刊：
影响因子：
11.2
通讯作者：
Reyburn HT
中科院分区：
文献类型：
--
作者：
Ashiru O;Boutet P;Fernández-Messina L;Agüera-González S;Skepper JN;Valés-Gómez M;Reyburn HT
活化受体NKG 2D的MHC I类相关链（MIC）A和MICB配体可从肿瘤细胞脱落，血清中这些可溶性分子的存在与免疫应答受损和疾病进展有关。最近，硫醇二硫化物异构酶和ADAM（去整合素和金属蛋白酶）基因家族的成员被鉴定为介导云母/B从细胞脱落的关键酶。在这里，我们报告了人类群体中最常表达的云母等位基因（云母 *008）脱落到外泌体中，外泌体是与质膜融合后分泌的小膜囊泡。尽管在胞外结构域中与其他云母/B分子相似，但云母 *008的预测跨膜和胞质结构域非常不同，并且这种差异似乎对从肿瘤细胞释放的模式至关重要。用含有云母 *008分子的外泌体处理自然杀伤（NK）细胞不仅触发了细胞表面NKG 2D的下调，还引起了NK细胞毒性的显著降低，这与靶细胞的NKG 2D配体表达无关。我们的研究结果揭示了癌症中NK抑制的机制，这可能有助于免疫逃逸和进展。
The MHC class I-related chain (MIC) A and MICB ligands for the activating receptor NKG2D can be shed from tumor cells, and the presence of these soluble molecules in sera is related with compromised immune response and progression of disease. Recently, thiol disulphide isomerases and members of the ADAM (a disintegrin and metalloproteinase) gene family were identified as key enzymes in mediating MICA/B shedding from cells. Here, we report shedding of the most frequently expressed MICA allele in human populations (MICA*008) into exosomes, small membrane vesicles that are secreted upon fusion with the plasma membrane. Although similar to other MICA/B molecules in the extracellular domain, the predicted transmembrane and cytoplasmic domains of MICA*008 are quite different, and this difference seemed to be critical for the mode of release from tumor cells. Treatment of natural killer (NK) cells with exosomes containing MICA*008 molecules not only triggered downregulation of NKG2D from the cell surface but also provoked a marked reduction in NK cytotoxicity that is independent of NKG2D ligand expression by the target cell. Our findings reveal a mechanism of NK suppression in cancer that may facilitate immune escape and progression.