Minimal requirement for induction of natural cytotoxicity and intersection of activation signals by inhibitory receptors
Minimal requirement for induction of natural cytotoxicity and intersection of activation signals by inhibitory receptors
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DOI：
10.1182/blood-2009-01-201632
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发表时间：
2009-09-24
期刊：
影响因子：
20.3
通讯作者：
Long, Eric O.
中科院分区：
文献类型：
--
作者：
Bryceson, Yenan T.;Ljunggren, Hans-Gustaf;Long, Eric O.
自然杀伤 (NK) 细胞对感染细胞和肿瘤细胞提供先天控制。多种受体与天然细胞毒性有关，但它们各自的贡献仍不清楚。在这里，我们研究了表达受体 NKG2D、DNAM-1、2B4、CD2 和 LFA-1 配体的果蝇细胞对原代静息人类 NK 细胞的激活。每个受体都能够诱导 LFA-1 的由内而外的信号，促进粘附，但没有诱导脱颗粒。相反，溶细胞颗粒的释放需要通过受体的共同接合来协同激活，如此处所示的 NKG2D 和 2B4。尽管 NKG2D 和 2B4 的结合不足以实现强烈的靶细胞裂解，但 LFA-1、NKG2D 和 2B4 的共同结合定义了天然细胞毒性的最低要求。值得注意的是，这些受体（包括 LFA-1）中的每一种所诱导的由内而外的信号传导均受到与 HLA-E 结合的受体 CD94/NKG2A 的抑制。 NKG2D 和 2B4 组合或 CD16 诱导的强由内而外信号可以克服 CD94/NKG2A 抑制。相反，这些受体诱导的脱颗粒仍然受到CD94/NKG2A的抑制。这些结果揭示了天然细胞毒性激活途径的多个层次，并且这些步骤与 LFA-1 的由内而外信号传导和颗粒释放信号一样独特，对 CD94/NKG2A 的抑制敏感。 （血。2009；114：2657-2666）
Natural killer (NK) cells provide innate control of infected and neoplastic cells. Multiple receptors have been implicated in natural cytotoxicity, but their individual contribution remains unclear. Here, we studied the activation of primary, resting human NK cells by Drosophila cells expressing ligands for receptors NKG2D, DNAM-1, 2B4, CD2, and LFA-1. Each receptor was capable of inducing inside-out signals for LFA-1, promoting adhesion, but none induced degranulation. Rather, release of cytolytic granules required synergistic activation through co-engagement of receptors, shown here for NKG2D and 2B4. Although engagement of NKG2D and 2B4 was not sufficient for strong target cell lysis, collective engagement of LFA-1, NKG2D, and 2B4 defined a minimal requirement for natural cytotoxicity. Remarkably, inside-out signaling induced by each one of these receptors, including LFA-1, was inhibited by receptor CD94/NKG2Abinding to HLA-E. Strong inside-out signals induced by the combination of NKG2D and 2B4 or by CD16 could overcome CD94/NKG2A inhibition. In contrast, degranulation induced by these receptors was still subject to inhibition by CD94/NKG2A. These results reveal multiple layers in the activation pathway for natural cytotoxicity and that steps as distinct as inside-out signaling to LFA-1 and signals for granule release are sensitive to inhibition by CD94/NKG2A. (Blood. 2009; 114: 2657-2666)