Research ArticleImmunology

NK cells integrate signals over large areas when building immune synapses but require local stimuli for degranulation

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Science Signaling  25 May 2021:
Vol. 14, Issue 684, eabe2740
DOI: 10.1126/scisignal.abe2740

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Ligand-patterned immune synapses

Natural killer (NK) cells execute virus-infected and tumor cells by forming immunological synapses with the target cells and releasing cytotoxic granules. The NK cell receptors LFA-1 and CD16 drive target cell recognition, synapse formation, and degranulation. Using artificial immune synapses (AIS) consisting of LFA-1 and CD16 ligands, Verron et al. found that the spatial distribution of receptor activation influenced the stability of synapses and subsequent degranulation. Although human NK cells formed synapses and properly positioned the lytic machinery on both dot- and donut-shaped AIS, degranulation did not occur in the central regions of donut-shaped AIS. The dependence of degranulation on local signaling suggests the existence of a late checkpoint for degranulation and suggests that target cells might be able to evade execution by controlling the spatial distribution of ligands (see also the Focus by Veillette).


Immune synapses are large-scale, transient molecular assemblies that serve as platforms for antigen presentation to B and T cells and for target recognition by cytotoxic T cells and natural killer (NK) cells. The formation of an immune synapse is a tightly regulated, stepwise process in which the cytoskeleton, cell surface receptors, and intracellular signaling proteins rearrange into supramolecular activation clusters (SMACs). We generated artificial immune synapses (AIS) consisting of synthetic and natural ligands for the NK cell–activating receptors LFA-1 and CD16 by microcontact printing the ligands into circular-shaped SMAC structures. Live-cell imaging and analysis of fixed human NK cells in this reductionist system showed that the spatial distribution of activating ligands influenced the formation, stability, and outcome of NK cell synapses. Whereas engagement of LFA-1 alone promoted synapse initiation, combined engagement of LFA-1 and CD16 was required for the formation of mature synapses and degranulation. Organizing LFA-1 and CD16 ligands into donut-shaped AIS resulted in fewer long-lasting, symmetrical synapses compared to dot-shaped AIS. NK cells spreading evenly over either AIS shape exhibited similar arrangements of the lytic machinery. However, degranulation only occurred in regions containing ligands that therefore induced local signaling, suggesting the existence of a late checkpoint for degranulation. Our results demonstrate that the spatial organization of ligands in the synapse can affect its outcome, which could be exploited by target cells as an escape mechanism.

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