Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
J Immunol. 2010 Oct 15;185(8):4698-704. doi: 10.4049/jimmunol.1001220. Epub 2010 Sep 10.
Natural cytotoxicity is achieved by polarized release of perforin and granzymes at the NK cell-target cell immunological synapse. Signals for granule polarization and degranulation can be uncoupled in NK cells, which raises the question of their respective sensitivity to inhibitory receptors. Expression of either HLA-C or HLA-E on the human cell line 721.221 blocked granule polarization, degranulation, and CD16-dependent MIP-1α secretion by NK cell clones that expressed inhibitory receptors of matching HLA specificity. To test inhibition of signals for polarization and degranulation separately, Drosophila S2 cells expressing ICAM-1 with either HLA-C or HLA-E were used. CD16-dependent degranulation and MIP-1α secretion were not fully inhibited, suggesting that other receptor-ligand interactions, which occur with 721.221 cells, contribute to inhibition. In contrast, HLA-C or HLA-E on S2 cells coexpressing ICAM-1 or ULBP1 were sufficient to block granule polarization induced by either LFA-1 or NKG2D, even during concomitant CD16-dependent degranulation. Similarly, expression of a ligand for NKR-P1A on S2 cells inhibited granule polarization but not CD16-induced degranulation. Therefore, granule polarization, rather than degranulation, is the preferred target of inhibitory receptors in NK cells.
自然细胞毒性是通过 NK 细胞-靶细胞免疫突触中极化释放穿孔素和颗粒酶来实现的。颗粒极化和脱颗粒的信号可以在 NK 细胞中解偶联，这引发了它们对抑制性受体的敏感性问题。在人类细胞系 721.221 上表达 HLA-C 或 HLA-E 会阻断 NK 细胞克隆的颗粒极化、脱颗粒和 CD16 依赖性 MIP-1α 分泌，这些克隆表达与 HLA 特异性匹配的抑制性受体。为了分别测试极化和脱颗粒信号的抑制作用，使用表达 ICAM-1 与 HLA-C 或 HLA-E 的果蝇 S2 细胞进行了实验。CD16 依赖性脱颗粒和 MIP-1α 分泌并未完全被抑制，这表明在与 721.221 细胞发生的其他受体-配体相互作用也有助于抑制作用。相比之下，S2 细胞共表达 ICAM-1 或 ULBP1 时表达的 HLA-C 或 HLA-E 足以阻断 LFA-1 或 NKG2D 诱导的颗粒极化，即使在同时发生 CD16 依赖性脱颗粒时也是如此。同样，S2 细胞上表达的 NKR-P1A 配体抑制颗粒极化，但不抑制 CD16 诱导的脱颗粒。因此，颗粒极化而不是脱颗粒是 NK 细胞中抑制性受体的首选靶标。
