Wang Huiming, Yang Di, Xu Wenyue, Wang Yiqin, Ruan Zhihua, Zhao Tingting, Han Junfeng, Wu Yuzhang
Institute of immunology, PLA, The Third Military Medical University, Chongqing 400038, PR China.
Immunol Lett. 2008 Oct 30;120(1-2):65-71. doi: 10.1016/j.imlet.2008.07.001. Epub 2008 Jul 29.
Upon ligation with its ligands, the activating receptor NKG2D stimulates or costimulates CD8(+) T cells or NK cells. The inducible gene MHC class I chain-related molecules (MICs), which belong to the NKG2D ligand family and usually initiate the process of lymphocyte activation, have been found to be broadly expressed on epithelial tumor cells. Sustained localized expression or release of soluble forms of MICs (sMICs) by tumor cells play key roles in tumor evasion via the impairment of T cell and NK cell functions. NKG2D is also expressed on the surface of CD3(+)CD56(+) NKT-like cells, which participate in tumor rejection via direct cytolysis. We speculated whether sMICs have the same impact on NKT-like cells. In this study, we demonstrated that in vitro killing by freshly isolated NKT-like cells was principally mediated by NKG2D, and the cytotoxic function of NKT-like cells isolated from cancer patients was obviously compromised. We found a significant correlation between elevated tumor-derived sMICs and down-modulation of NKG2D expression on NKT-like cell surfaces in human ovarian cancer and prostate cancer patients. We determined that elevated serum sMIC impairs the lytic activity via downregulation of the NKG2D receptor because incubation of NKT-like cells with sera obtained from cancer patients down-modulated surface NKG2D expression, whereas the addition of neutralizing anti-MIC mAbs restored surface NKG2D expression. We suggest that tumors shedding MICs may promote immune evasion by impairing NKT-like cell cytotoxicity.
激活受体NKG2D与其配体结合后，可刺激或共刺激CD8(+) T细胞或自然杀伤（NK）细胞。属于NKG2D配体家族的诱导型基因MHC I类链相关分子（MIC）通常启动淋巴细胞激活过程，已发现其在上皮肿瘤细胞上广泛表达。肿瘤细胞持续局部表达或释放可溶性MIC（sMIC）通过损害T细胞和NK细胞功能在肿瘤逃逸中起关键作用。NKG2D也表达于CD3(+)CD56(+) NKT样细胞表面，这些细胞通过直接细胞溶解参与肿瘤排斥反应。我们推测sMIC对NKT样细胞是否有相同影响。在本研究中，我们证明新鲜分离的NKT样细胞的体外杀伤主要由NKG2D介导，且从癌症患者分离的NKT样细胞的细胞毒性功能明显受损。我们发现人卵巢癌和前列腺癌患者肿瘤来源的sMIC升高与NKT样细胞表面NKG2D表达下调之间存在显著相关性。我们确定血清sMIC升高通过下调NKG2D受体损害溶解活性，因为用癌症患者血清孵育NKT样细胞可下调表面NKG2D表达，而添加中和抗MIC单克隆抗体可恢复表面NKG2D表达。我们认为脱落MIC的肿瘤可能通过损害NKT样细胞的细胞毒性促进免疫逃逸。
