Abstract
Author SummaryNatural Killer (NK) cells are immune cells that can recognise and kill virus-infected and cancerous cells. This killing requires an intercellular contact —termed an immune synapse—between the NK cell and its target cell through which molecules can be delivered to trigger lysis. Reorganisation of the NK cell cytoskeleton is essential for the delivery and release at the synapse of granules containing the cytolytic molecules. Understanding precisely how the cytoskeleton is involved in these cytolytic events has been hampered by our inability to resolve cytoskeletal structure at immune synapses by conventional light microscopy. Very recent advances in imaging technology have now provided the resolving power to see previously undetectable cellular structures. Here, we have used 3D super-resolution imaging to observe the structure of the actin cytoskeleton at the NK immune synapse. We found that a dense mesh of actin underlies the immune synapse and that it is remodelled upon NK cell activation. Domains within the actin meshwork open up specifying where the lytic granules dock and also where the microtubule-organising centre moves towards. Thus, actin remodelling occurs at the immune synapse during secretion and this may be important for the regulation of lytic granule secretion.
Highlights
Natural Killer (NK) cells are lymphocytes of the innate immune system that protect against viral infection and tumour progression via contact-dependent cellular cytotoxicity and the release of immune mediators such as cytokines [1]
Natural Killer (NK) cells are immune cells that can recognise and kill virus-infected and cancerous cells. This killing requires an intercellular contact —termed an immune synapse—between the NK cell and its target cell through which molecules can be delivered to trigger lysis
Understanding precisely how the cytoskeleton is involved in these cytolytic events has been hampered by our inability to resolve cytoskeletal structure at immune synapses by conventional light microscopy
Summary
Natural Killer (NK) cells are lymphocytes of the innate immune system that protect against viral infection and tumour progression via contact-dependent cellular cytotoxicity and the release of immune mediators such as cytokines [1]. NK cell cytotoxicity involves the direct killing of virus-infected or tumour cells through the polarised release of cytolytic molecules from specialised secretory organelles called lytic granules [2,3]. To ensure that NK cell killing is only directed towards appropriate target cells, NK cell activation and lytic granule release are tightly regulated [4]. The balance of activating and inhibitory signals at the immune synapse is translated into an appropriate NK cell response [10]. An activating or cytolytic synapse is assembled and downstream NK cell effector functions are triggered, such as lytic granule polarisation and directed secretion towards the target cell [11,12,13,14,15,16]. It is well established that actin polymerisation is important for degranulation [13], how the temporal and spatial organisation of actin, as well as activating receptors, facilitates lytic granule secretion remains ill-defined
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