Natural killer cells can discriminate between normal cells and cells that do not express adequate amounts of major histocompatibility complex (MHC) class I molecules. The discovery, both in mouse and in human, of MHC-specific inhibitory receptors clarified the molecular basis of this important NK cell function. However, the triggering receptors responsible for positive NK cell stimulation remained elusive until recently. Some of these receptors have now been identified in humans, thus shedding some light on the molecular mechanisms involved in NK cell activation during the process of natural cytotoxicity. Three novel, NK-specific, triggering surface molecules (NKp46, NKp30, and NKp44) have been identified. They represent the first members of a novel emerging group of receptors collectively termed natural cytotoxicity receptors (NCR). Monoclonal antibodies (mAbs) to NCR block to differing extents the NK-mediated lysis of various tumors. Moreover, lysis of certain tumors can be virtually abrogated by the simultaneous masking of the three NCRs. There is a coordinated surface expression of the three NCRs, their surface density varying in different individuals and also in the NK cells isolated from a given individual. A direct correlation exists between the surface density of NCR and the ability of NK cells to kill various tumors. NKp46 is the only NCR involved in human NK-mediated killing of murine target cells. Accordingly, a homologue of NKp46 has been detected in mouse. Molecular cloning of NCR revealed novel members of the Ig superfamily displaying a low degree of similarity to each other and to known human molecules. NCRs are coupled to different signal transducing adaptor proteins, including CD3 zeta, Fc epsilon RI gamma, and KARAP/DAP12. Another triggering NK receptor is NKG2D. It appears to play either a complementary or a synergistic role with NCRs. Thus, the triggering of NK cells in the process of tumor cell lysis may often depend on the concerted action of NCR and NKG2D. In some instances, however, it may uniquely depend upon the activity of NCR or NKG2D only. Strict NKG2D-dependency can be appreciated using clones that, in spite of their NCR(dull) phenotype, efficiently lyse certain epithelial tumors or leukemic cell lines. Other triggering surface molecules including 2B4 and the novel NKp80 appear to function as coreceptors rather than as true receptors. Indeed, they can induce natural cytotoxicity only when co-engaged with a triggering receptor. While an altered expression or function of NCR or NKG2D is being explored as a possible cause of immunological disorders, 2B4 dysfunction has already been associated with a severe form of immunodeficiency. Indeed, in patients with the X-linked lymphoproliferative disease, the inability to control Epstein-Barr virus infections may be consequent to a major dysfunction of 2B4 that exerts inhibitory instead of activating functions.

中文翻译：

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激活参与人类自然杀伤细胞介导的细胞溶解的受体和辅助受体。

自然杀伤细胞可以区分正常细胞和不表达足够量的主要组织相容性复合物 (MHC) I 类分子的细胞。在小鼠和人类中发现的 MHC 特异性抑制受体阐明了这一重要 NK 细胞功能的分子基础。然而，直到最近，负责阳性 NK 细胞刺激的触发受体仍然难以捉摸。这些受体中的一些现在已经在人类中被鉴定出来，从而揭示了在自然细胞毒性过程中参与 NK 细胞活化的分子机制。已鉴定出三种新型 NK 特异性触发表面分子（NKp46、NKp30 和 NKp44）。它们代表了一组新出现的受体的第一批成员，这些受体统称为天然细胞毒性受体 (NCR)。针对 NCR 的单克隆抗体 (mAb) 在不同程度上阻断了 NK 介导的各种肿瘤的裂解。此外，某些肿瘤的裂解实际上可以通过同时掩盖三个 NCR 来消除。三种 NCR 有一个协调的表面表达，它们的表面密度在不同的个体中以及在从给定个体分离的 NK 细胞中也不同。NCR 的表面密度与 NK 细胞杀死各种肿瘤的能力之间存在直接相关性。NKp46 是唯一参与人类 NK 介导的鼠靶细胞杀伤的 NCR。因此，已在小鼠中检测到 NKp46 的同源物。NCR 的分子克隆揭示了 Ig 超家族的新成员，它们彼此之间以及与已知人类分子的相似性较低。NCR 与不同的信号转导衔接蛋白偶联，包括 CD3 zeta、Fc epsilon RI γ 和 KARAP/DAP12。另一种触发 NK 受体是 NKG2D。它似乎与 NCR 起互补或协同作用。因此，肿瘤细胞裂解过程中 NK 细胞的触发可能往往取决于 NCR 和 NKG2D 的协同作用。然而，在某些情况下，它可能仅取决于 NCR 或 NKG2D 的活性。使用克隆可以理解严格的 NKG2D 依赖性，尽管它们具有 NCR（钝）表型，但有效地裂解某些上皮肿瘤或白血病细胞系。包括 2B4 和新型 NKp80 在内的其他触发表面分子似乎起到辅助受体的作用，而不是真正的受体。事实上，它们只有在与触发受体共同作用时才能诱导天然细胞毒性。虽然正在探索 NCR 或 NKG2D 的表达或功能改变作为免疫疾病的可能原因，但 2B4 功能障碍已经与严重形式的免疫缺陷有关。事实上，在患有 X 连锁淋巴组织增生性疾病的患者中，无法控制 Epstein-Barr 病毒感染可能是由于 2B4 发挥抑制而不是激活功能的主要功能障碍所致。