HDAC调节NK细胞主要激活受体NKG2D表达的分子机制

NKG2D is a major activating recptor of natural killer (NK) cells, and also is the first receptor of innate immunity in tumor immunesurveillance.NK cell recognition and killing activity correlate with receptors expression on the cell surface. NKG2D plays a crucial role in NK cell-mediated lysis through recognising and binding to corresponding ligands,MHC class I-related gene A (MICA) and B (MICB), and UL16-binding proteins 1 through 5 (ULBP1-5).However, so far, little is known about molecular regulation of NKG2D expression on NK cell surface, this heavily hampers NK cell applications.In previous studies, we found that histone deacetylases (HDACs) regulated NKG2D expression on NK cell surface through two sides: some HDACs promote NKG2D expression, and some HDACs inhibit NKG2D expression.The promotion maybe correlates with HDACs -mediated signal transducer and activator of transcription-3 (STAT3) phosphorylation, and the inhibition maybe correlates with HDACs-mediated histones deacetylation.In this program, we will identify the HDAC molecules that promote and inhibit NKG2D expression on human NK cell surface, and investigate their regulating mechanisms, respectively. After the identifiaction of HDACs, we will use the HDAC molecules or their shRNA to modify NK cells, and use the modified NK cells for cancer immunotherapy. The succesful performance of this program will not only elucidate the molucular mechanisms of HDAC mediated regulation of NKG2D expression on NK cell surface and perfect NK cell molecular regulations, but also provide a new theory and a novel strategy for NK cell based antivirus and antitumor immunotherapy.

NKG2D是自然杀伤细胞（NK细胞）最主要的激活受体，也是肿瘤免疫监视过程中第一位的固有免疫受体。NKG2D表达与NK细胞的免疫识别和靶细胞杀伤密切相关。然而，至今对于NK细胞表面NKG2D表达调控分子机制不太清楚，这极大地限制了NK细胞的有效利用。我们早期的研究表明，HDAC分子对NK细胞表面NKG2D表达具有双重调节作用：某些HDAC促进NKG2D表达，某些HDAC抑制NKG2D表达。其促进效应可能与其调节STAT3磷酸化有关，而其抑制效应可能与其组蛋白去乙酰修饰有关。本项目将鉴定促进和抑制NKG2D表达的HDAC分子，分别阐明其相应的分子调控机理，并针对鉴定的HDAC分子对NK细胞进行遗传修饰，进行以HDAC分子修饰为基础的NK细胞免疫治疗研究。项目的实施不仅将阐明HDAC调节NKG2D表达的分子机理，完善NK细胞调节机制，而且将为NK细胞基础的抗病毒、抗肿瘤治疗提供新理论和新策略。

NKG2D是NK细胞（自然杀伤细胞）最主要的激活受体，与NK细胞的免疫识别和杀伤密切相关。本项目中我们发现，STAT3激活后可以结合到NKG2D转录起始位点上游；STAT3激活剂IL-10和IL-21增加这种结合，从而增加NKG2D表达，而STAT3抑制剂则减少这种增加。STAT3突变患者NK细胞表面NKG2D表达没有明显改变，但IL-10和IL-21刺激后并不显著增加NKG2D表达；进一步研究表明，HDAC3可以与STAT3结合，HDAC3基因敲除后IL-21对NK细胞增殖无明显影响，但对NKG2D表达调节显著降低。这些结果提示HDAC3去乙酰化酶活性对于STAT3磷酸化至关重要，而STAT3磷酸化水平又与NKG2D表达直接相关，这一HDAC3-STAT3-NKG2D分子信号通路的初步确立对阐明NKG2D的分子调节机制具有重要意义。