Homotypic Cell to Cell Cross-talk Among Human Natural Killer Cells Reveals Differential and Overlapping Roles of 2B4 and CD2
Homotypic Cell to Cell Cross-talk Among Human Natural Killer Cells Reveals Differential and Overlapping Roles of 2B4 and CD2
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DOI：
10.1074/jbc.m110.137976
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发表时间：
2010-12-31
影响因子：
4.8
通讯作者：
Lee, Kyung-Mi
中科院分区：
文献类型：
--
作者：
Kim, Eun-Ok;Kim, Tae-Jin;Lee, Kyung-Mi
人类自然杀伤（NK）细胞在其表面表达丰富水平的2B 4和CD 2。它们的反受体CD 48和CD 58也在NK细胞表面表达，这引起了关于潜在2B 4/CD 48和CD 2/CD 58相互作用的功能后果的问题。使用对每个受体特异性的阻断抗体，我们证明了2B 4/CD 48和CD 2/CD 58相互作用对于NK效应器功能的发展是必不可少的：细胞毒性和细胞因子分泌。然而，只有2B 4/CD 48，而不是CD 2/CD 58，相互作用被证明是至关重要的最佳NK细胞增殖响应白细胞介素（IL）-2。在不存在2B 4/CD 48或CD 2/CD 58相互作用的情况下培养的IL-2激活的NK细胞在肿瘤靶点暴露后诱导细胞内钙动员和随后ERK激活的能力严重受损，表明导致细胞溶解和干扰素（IFN）-γ分泌受损的NK受体早期信号传导途径受到抑制。然而，这些缺陷并不能完全解释在不存在2B 4/CD 48相互作用的情况下NK细胞增殖降低的原因，因为抗CD 2或抗CD 58单克隆抗体（mAb）处理的NK细胞显示出有缺陷的信号传导和效应子功能，在IL-2刺激后显示出正常增殖。这些结果表明导致细胞增殖和细胞毒性/细胞因子释放的途径之间的信号传导分歧，其可以在IL-2驱动的NK细胞活化期间由2B 4和CD 2差异调节。总的来说，这些结果揭示了通过2B 4/CD 48和CD 2/CD 58对的同型NK细胞对NK细胞串扰的重要性，并进一步呈现了它们在人NK细胞中的差异和重叠作用。
Human natural killer (NK) cells express an abundant level of 2B4 and CD2 on their surface. Their counter-receptors, CD48 and CD58, are also expressed on the NK cell surface, raising a question about the functional consequences of potential 2B4/CD48 and CD2/CD58 interactions. Using blocking antibodies specific to each receptor, we demonstrated that both 2B4/CD48 and CD2/CD58 interactions were essential for the development of NK effector functions: cytotoxicity and cytokine secretion. However, only 2B4/CD48, but not CD2/CD58, interactions were shown to be critical for the optimal NK cell proliferation in response to interleukin (IL)-2. IL-2-activated NK cells cultured in the absence of 2B4/CD48 or CD2/CD58 interactions were severely impaired for their ability to induce intracellular calcium mobilization and subsequent ERK activation upon tumor target exposure, suggesting that the early signaling pathway of NK receptors leading to impaired cytolysis and interferon (IFN)-gamma secretion was inhibited. Nevertheless, these defects did not fully account for the reduced proliferation of NK cells in the absence of 2B4/CD48 interactions, because anti-CD2 or anti-CD58 monoclonal antibody (mAb)-treated NK cells, showing defective signaling and effector functions, displayed normal proliferation upon IL-2 stimulation. These results propose the signaling divergence between pathways leading to cell proliferation and cytotoxicity/cytokine release, which can be differentially regulated by 2B4 and CD2 during IL-2-driven NK cell activation. Collectively, these results reveal the importance of homotypic NK-to-NK cell cross-talk through 2B4/CD48 and CD2/CD58 pairs and further present their differential and overlapping roles in human NK cells.