The immune synapse clears and excludes molecules above a size threshold.
The immune synapse clears and excludes molecules above a size threshold.
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DOI：
10.1038/ncomms6479
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发表时间：
2014-11-19
影响因子：
16.6
通讯作者：
Davis, Daniel M.
中科院分区：
文献类型：
--
作者：
Cartwright, Adam N. R.;Griggs, Jeremy;Davis, Daniel M.
自然杀伤细胞通过促进信号整合和定向分泌的免疫突触（IS）处的相互作用来评估靶细胞健康。在这里，我们测试是否IS也作为一个垫圈的功能。定量荧光显微镜的纳米级葡聚糖内的突触形成的各种效应-靶细胞共轭物揭示，分子被排除在一个大小依赖性的方式在激活突触。尺寸≤4 nm的葡聚糖进出IS，但对于尺寸为10-13 nm的葡聚糖，进入显著减少（>50%），并且几乎完全排除≥32 nm的葡聚糖。F-肌动蛋白的解聚消除了排斥。出乎意料的是，随着IS以拉链状方式组装，较大尺寸的葡聚糖被清除。单克隆抗体也被排除在IS之外，但较小的单域抗体能够穿透。因此，IS可以清除和排除大于尺寸阈值的分子，并且设计用于靶向突触细胞因子或细胞毒性蛋白的药物必须符合这些尺寸。 自然杀伤细胞可以通过与另一个细胞形成的免疫突触来开启或关闭。在这里，作者表明，当自然杀伤细胞被激活时，免疫突触也可以以大小依赖的方式清除和排除细胞外分子，包括抗体。
Natural killer cells assess target cell health via interactions at the immune synapse (IS) that facilitates signal integration and directed secretion. Here we test whether the IS also functions as a gasket. Quantitative fluorescence microscopy of nanometer-scale dextrans within synapses formed by various effector-target cell conjugates reveal that molecules are excluded in a size-dependent manner at activating synapses. Dextran sized ≤4 nm move in and out of the IS, but access is significantly reduced (by >50%) for dextran sized 10–13 nm, and dextran ≥32 nm is almost entirely excluded. Depolymerization of F-actin abrogated exclusion. Unexpectedly, larger-sized dextrans are cleared as the IS assembles in a zipper-like manner. Monoclonal antibodies are also excluded from the IS but smaller single-domain antibodies are able to penetrate. Therefore, the IS can clear and exclude molecules above a size threshold, and drugs designed to target synaptic cytokines or cytotoxic proteins must fit these dimensions. Natural killer cells can be switched on or off by the immune synapse formed with another cell. Here, the authors show that when a natural killer cell is activated, the immune synapse also functions to clear and exclude extracellular molecules, including antibodies, in a size-dependent manner.
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影响因子：
3.7
作者：
Koehler, Karsten;Xiong, Shiqiu;Davis, Daniel M.
通讯作者：
Davis, Daniel M.
影响因子：
15.3
作者：
Davis, DM;Mandelboim, O;Strominger, JL
通讯作者：
Strominger, JL
影响因子：
3.4
作者：
Alakoskela, Juha-Matti;Koner, Apurba L.;Davis, Daniel M.
通讯作者：
Davis, Daniel M.
影响因子：
32.4
作者：
Metkar, SS;Wang, BK;Froelich, CJ
通讯作者：
Froelich, CJ
影响因子：
56.9
作者：
EALICK, SE;COOK, WJ;BUGG, CE
通讯作者：
BUGG, CE