Helmholtz-Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Institut für Molekulare Immunologie, München, Germany.
Eur J Immunol. 2010 Feb;40(2):494-504. doi: 10.1002/eji.200939937.
The role of NK cells in the control of endogenously arising tumors is still unclear. We monitored activation and effector functions of NK cells in a c-myc-transgenic mouse model of spontaneously arising lymphoma. At early stages, tumors demonstrated reduced MHC class I expression and increased expression of natural killer group 2D ligands (NKG2D-L). NK cells in these tumors showed an activated phenotype that correlated with the loss of tumor MHC class I. With increasing tumor load however, NK-cell effector functions became progressively paralyzed or exhausted. In later stages of disease, tumors re-expressed MHC class I and lost NKG2D-L, suggesting a role of these two signals for NK cell-mediated tumor control. Testing a panel of lymphoma cell lines expressing various MHC class I and NKG2D-L levels suggested that NK cell-dependent tumor control required a priming and a triggering signal that were provided by MHC class I down-regulation and by NKG2D-L, respectively. Deleting either of the "two signals" resulted in tumor escape. At early disease stages, immune stimulation through TLR-ligands in vivo efficiently delayed lymphoma growth in a strictly NK cell-dependent manner. Thus, NK-receptor coengagement is crucial for NK-cell functions in vivo and especially for NK cell-mediated tumor surveillance.
自然杀伤细胞（NK 细胞）在控制内源性肿瘤中的作用尚不清楚。我们在一个 c-myc 转基因小鼠自发性淋巴瘤模型中监测 NK 细胞的激活和效应功能。在早期阶段，肿瘤表现出 MHC Ⅰ类分子表达降低和自然杀伤细胞组 2D 配体（NKG2D-L）表达增加。这些肿瘤中的 NK 细胞表现出与肿瘤 MHC Ⅰ类分子缺失相关的激活表型。然而，随着肿瘤负荷的增加，NK 细胞的效应功能逐渐瘫痪或衰竭。在疾病的后期阶段，肿瘤重新表达 MHC Ⅰ类分子并失去 NKG2D-L，表明这两种信号在 NK 细胞介导的肿瘤控制中发挥作用。通过检测一系列表达不同 MHC Ⅰ类和 NKG2D-L 水平的淋巴瘤细胞系，提示 NK 细胞依赖的肿瘤控制需要一个启动和触发信号，分别由 MHC Ⅰ类分子下调和 NKG2D-L 提供。删除其中任何一个“两个信号”都会导致肿瘤逃逸。在疾病早期，通过 TLR 配体在体内进行免疫刺激，能够以严格依赖 NK 细胞的方式有效延缓淋巴瘤的生长。因此，NK 受体的共结合对于 NK 细胞在体内的功能至关重要，特别是对于 NK 细胞介导的肿瘤监视。
