The integrin LFA-1 is essential for efficient activation and for cytotoxicity of NK cells because it initiates the assembly of the immunological synapse and mediates firm adhesion to the target. LFA-1 is also needed to polarize the cytotoxic machinery of the NK cell toward the target cell. The binding affinity and avidity of integrins can be regulated via inside-out signals from other receptors. In this article, we investigate the signals necessary to activate LFA-1 in human NK cells. Our data show that LFA-1 has a low ligand-binding activity in resting human NK cells, but it can be stimulated by triggering activating receptors, such as 2B4 or CD16, or by coactivation of different receptor combinations. Short-term stimulation of freshly isolated NK cells with cytokines, such as IL-15, IL-12, or IL-18, does not activate LFA-1 but increases the responsiveness of the cells to subsequent receptor stimulation. Different NK cell subsets vary in their ability to induce LFA-1 binding activity after activating receptor stimulation. Interestingly, the NK cell subsets that are more mature and possess higher cytotoxic potential also show the highest activation of LFA-1, which correlated with the expression of the small calcium-binding protein S100A4. Our data suggest that regulation of LFA-1 is one reason for the different activity of NK cells during differentiation.

译文

:整联蛋白LFA-1对于NK细胞的有效激活和细胞毒性至关重要,因为它启动了免疫突触的组装并介导了对靶标的牢固粘附。还需要LFA-1才能使NK细胞的细胞毒性机制向靶细胞极化。整联蛋白的结合亲和力和亲合力可以通过来自其他受体的由内而外的信号来调节。在本文中,我们研究了激活人NK细胞中LFA-1所必需的信号。我们的数据表明,LFA-1在静止的人NK细胞中具有较低的配体结合活性,但可以通过触发活化受体(例如2B4或CD16)或通过共活化不同受体组合来刺激。用细胞因子(例如IL-15,IL-12或IL-18)短期刺激新鲜分离的NK细胞不会激活LFA-1,但会增加细胞对随后受体刺激的反应性。激活受体刺激后,不同的NK细胞亚群诱导LFA-1结合活性的能力各不相同。有趣的是,更成熟且具有较高细胞毒性潜能的NK细胞亚群也显示了LFA-1的最高活化,这与小钙结合蛋白S100A4的表达有关。我们的数据表明,LFA-1的调节是分化过程中NK细胞活性不同的原因之一。

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