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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    Immunology and Cell Biology 01/2014; 92(3). DOI:10.1038/icb.2013.96 · 4.15 Impact Factor
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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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    Frontiers in Plant Science 12/2013; 4:503. DOI:10.3389/fpls.2013.00503 · 3.95 Impact Factor
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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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    ABSTRACT: Target cell recognition by cytotoxic lymphocytes implies the simultaneous engagement and clustering of adhesion and activating receptors followed by the activation of an array of signal transduction pathways. The cytotoxic immune synapse represents the highly specialized dynamic interface formed between the cytolytic effector and its target that allows temporal and spatial integration of signals responsible for a defined sequence of processes culminating with the polarized secretion of lytic granules. Over the last decades, much attention has been given to the molecular signals coupling receptor ligation to the activation of cytolytic machinery. Moreover, in the last 10 years the discovery of genetic defects affecting cytotoxic responses greatly boosted our knowledge on the molecular effectors involved in the regulation of discrete phases of cytotoxic process at post-receptor levels. More recently, the use of super resolution and total internal reflection fluorescence imaging technologies added new insights on the dynamic reorganization of receptor and signaling molecules at lytic synapse as well as on the relationship between granule dynamics and cytoskeleton remodeling. To date we have a solid knowledge of the molecular mechanisms governing granule movement and secretion, being not yet fully unraveled the machinery that couples early receptor signaling to the late stage of synapse remodeling and granule dynamics. Here we highlight recent advances in our understanding of the molecular mechanisms acting in the activation of cytolytic machinery, also discussing similarities and differences between Natural killer cells and cytotoxic CD8(+) T cells.
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