Natural killer cell immune synapse formation and cytotoxicity are controlled by tension of the target interface.
Natural killer cell immune synapse formation and cytotoxicity are controlled by tension of the target interface.
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DOI：
10.1242/jcs.258570
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发表时间：
2021-04-01
影响因子：
4
通讯作者：
Davis DM
中科院分区：
文献类型：
--
作者：
Friedman D;Simmonds P;Hale A;Bere L;Hodson NW;White MRH;Davis DM
自然杀伤(NK)细胞可以通过裂解的免疫突触杀死感染或转化的细胞。患病细胞可能会表现出机械特性的改变，但这如何影响NK细胞的反应性尚不清楚。我们报道，与软的(1 kpa)平板底物相比，刚性(142kPa)更有效地刺激人NK细胞分泌颗粒酶A和B、Fas L(也称为FasLG)、颗粒溶素和干扰素DNA。为了创造确定硬度的替代球形靶点，海藻酸钠被用来合成软的(9 kpa)、中等的(34 kpa)或硬的(254 kpa)细胞大小的珠子，包覆着抗激活受体NKp30(也称为NCR3)和整合素LFA-1(也称为ITGAL)的抗体。相对于硬珠，NK细胞表现出更多的脱颗粒。针对软靶，微管组织中心和裂解颗粒的极化受到损害，从而导致不稳定运动的形成。因此，通过改变目标硬度来表征免疫突触的机械敏感性，我们将软目标识别为NK细胞识别的盲点。对改变的靶标刚性的影响的分析表明，表达激活配体的软靶不会诱导细胞溶解所需的自然杀伤细胞机制的极化。
Natural killer (NK) cells can kill infected or transformed cells via a lytic immune synapse. Diseased cells may exhibit altered mechanical properties but how this impacts NK cell responsiveness is unknown. We report that human NK cells were stimulated more effectively to secrete granzymes A and B, FasL (also known as FasLG), granulysin and IFNγ, by stiff (142 kPa) compared to soft (1 kPa) planar substrates. To create surrogate spherical targets of defined stiffness, sodium alginate was used to synthesise soft (9 kPa), medium (34 kPa) or stiff (254 kPa) cell-sized beads, coated with antibodies against activating receptor NKp30 (also known as NCR3) and the integrin LFA-1 (also known as ITGAL). Against stiff beads, NK cells showed increased degranulation. Polarisation of the microtubule-organising centre and lytic granules were impaired against soft targets, which instead resulted in the formation of unstable kinapses. Thus, by varying target stiffness to characterise the mechanosensitivity of immune synapses, we identify soft targets as a blind spot in NK cell recognition. Analyses of the impact of altered target rigidity reveal that soft targets expressing activating ligands do not induce polarisation of natural killer cellular machinery required for cytolysis.