Natural Killer Cell Lytic Granule Secretion Occurs through a Pervasive Actin Network at the Immune Synapse

National Jewish Medical and Research Center/Howard Hughes Medical Institute, United States of America
PLoS Biology (Impact Factor: 9.34). 09/2011; 9(9):e1001151. DOI: 10.1371/journal.pbio.1001151
Source: PubMed


Author Summary
The immune system's natural killer cells eliminate diseased cells in the body. They do so by secreting toxic molecules directly towards the diseased cells, so causing their death. This process is essential for the host organism to defend itself against infectious diseases. The interface between the natural killer cell and its target—the lytic immunological synapse—forms by close apposition of the surface membranes of the two cells. It is characterized by coordinated rearrangement of proteins to allow lytic granules, which contain the toxic molecules, to fuse with the cell surface at the synapse. Given the large size of the granules, one challenge the natural killer cell faces is how to contend with network of actin filaments just under the cell surface, which potentially could pose a barrier to secretion. The current model proposes large-scale clearing of actin filaments from the center of the immunological synapse to provide granules access to the synaptic membrane. By using very high-resolution imaging techniques, we now demonstrate that actin filaments are present throughout the synapse and that natural killer cells overcome the actin barrier not by wholesale clearing but by making minimally sufficient conduits in the actin network. This suggests a model in which granules access the surface membrane by means of specific and facilitated contact with the actin cytoskeleton.

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    • "It seems likely, based on the presence of actin nucleating factors at the synapse, that F-actin is dynamic and is likely undergoing continual remodeling. This may contribute to conduit kinetics, as has been suggested by analyses of synaptic plane actin dynamics using total internal reflection fluorescence imaging.92 "
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    • "One of the biggest changes to our current understanding of membrane heterogeneity has been an elevation of the role of the cytoskeleton (Edidin, 2006). The cortical actin mesh has frequently been a target for new super-resolution based imaging methods, for example 3D PALM (Xu et al., 2012, 2013), SIM (Brown et al., 2011) and STED (Rak et al., 2011). The density and dynamics of the cortical actin network make this structure a defining feature of cell membranes. "
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    • "Recently, the model of NK cells secreting lytic granules through a central region devoid of F-actin has been exceeded. A couple of companion papers (12, 13), both using very high-resolution imaging techniques, reveal that F-actin forms a pervasive network at the synapse, and that following activating receptor engagement, lytic granules are secreted through the filamentous network by accessing minimally sufficient sized clearances instead of a large-scale clearing of actin filaments. Such remodeling of cortical actin occurs within the central region of the synapse establishing secretory domain where lytic granules dock. "
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