Kaufman D S, Schoon R A, Robertson M J, Leibson P J
Department of Immunology, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
Proc Natl Acad Sci U S A. 1995 Jul 3;92(14):6484-8. doi: 10.1073/pnas.92.14.6484.
Many studies have characterized the transmembrane signaling events initiated after T-cell antigen receptor recognition of major histocompatibility complex (MHC)-bound peptides. Yet, little is known about signal transduction from a set of MHC class I recognizing receptors on natural killer (NK) cells whose ligation dramatically inhibits NK cell-mediated killing. In this study we evaluated the influence of MHC recognition on the proximal signaling events in NK cells binding tumor targets. We utilized two experimental models where NK cell-mediated cytotoxicity was fully inhibited by the recognition of specific MHC class I molecules. NK cell binding to either class I-deficient or class I-transfected target cells initiated rapid protein tyrosine kinase activation. In contrast, whereas NK cell binding to class I-deficient targets led to inositol phosphate release and increased intracellular free calcium ([Ca2+]i), NK recognition of class I-bearing targets did not induce the activation of these phospholipase C-dependent signaling events. The recognition of class I by NK cells clearly had a negative regulatory effect since blocking this interaction using anti-class I F(ab')2 fragments increased inositol 1,4,5-trisphosphate release and [Ca2+]i and increased the lysis of the targets. These results suggest that one of the mechanisms by which NK cell recognition of specific MHC class I molecules can block the development of cell-mediated cytotoxicity is by inhibiting specific critical signaling events.
许多研究已对T细胞抗原受体识别主要组织相容性复合体（MHC）结合肽后引发的跨膜信号转导事件进行了特征描述。然而，对于自然杀伤（NK）细胞上一组识别MHC I类分子的受体的信号转导却知之甚少，这些受体的连接会显著抑制NK细胞介导的杀伤作用。在本研究中，我们评估了MHC识别对NK细胞结合肿瘤靶标时近端信号转导事件的影响。我们利用了两种实验模型，其中NK细胞介导的细胞毒性因识别特定的MHC I类分子而被完全抑制。NK细胞与I类缺陷或I类转染的靶细胞结合会引发快速的蛋白酪氨酸激酶激活。相比之下，虽然NK细胞与I类缺陷靶标结合会导致肌醇磷酸释放并增加细胞内游离钙（[Ca2+]i），但NK细胞对携带I类分子的靶标的识别并未诱导这些依赖磷脂酶C的信号转导事件的激活。NK细胞对I类分子的识别显然具有负调节作用，因为使用抗I类F(ab')2片段阻断这种相互作用会增加肌醇1,4,5-三磷酸释放和[Ca2+]i，并增加靶标的裂解。这些结果表明，NK细胞识别特定MHC I类分子从而阻断细胞介导的细胞毒性发展的机制之一是抑制特定的关键信号转导事件。
