Formation and Function of the Lytic NK‑Cell Immunological Synapse
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REVIEWS Formation and function of the lytic NK-cell immunological synapse Jordan S. Orange Abstract | The natural killer (NK)-cell immunological synapse is the dynamic interface formed between an NK cell and its target cell. Formation of the NK-cell immunological synapse involves several distinct stages, from the initiation of contact with a target cell to the directed delivery of lytic-granule contents for target-cell lysis. Progression through the individual stages is regulated, and this tight regulation underlies the precision with which NK cells select and kill susceptible target cells (including virally infected cells and cancerous cells) that they encounter during their routine surveillance of the body. ‘Danger’ signals Natural killer (NK) cells are lymphocytes of the innate of lytic-granule contents in NK cells compared with the Agents that alert the immune immune system that elicit effector functions following process in CTLs. Indeed, direct comparisons between system to danger and thereby the ligation of germline-encoded receptors. In humans, the cytolytic process in NK cells and CTLs have identified promote the generation of NK cells are able to deliver a response immediately after important kinetic and mechanistic differences2. immune responses. Danger recognizing specific signals, including stress signals, The induction of many NK-cell effector functions, signals can be associated with microbial invaders (exogenous ‘danger’ signals or signals from molecules of foreign including cytotoxicity, requires that the NK cell contacts danger signals), and can also origin. They were originally described as having rapid its target cell. This ensures precise targeting of the cytolytic be produced or expressed by cell-mediated cytotoxicity. However, they are now also process to a single diseased cell in a tissue without affect- damaged cells (endogenous known to promote slower receptor-mediated apopto- ing its neighbouring cells. The events that occur following danger signals). sis, to provide contact-dependent co-stimulation and the interaction between a cytolytic cell and its target cell to efficiently produce soluble mediators, including have been well studied. They include the delivery and cytokines. NK cells therefore participate in the defence secretion of cytolytic effector molecules at the interface against infections, the regulation of immune responses that is formed between the cytotoxic cell and its target cell and the surveillance of stressed or cancerous cells through a process known as directed secretion. (reviewed in REF. 1). Although these functions are not Our understanding of directed secretion for cyto- unique to NK cells, they use NK-cell-specific receptor toxicity has been advanced by the discovery of the systems, and the ability to mediate effector functions immunological synapse. The immunological synapse rapidly without the need to develop further is a key was originally defined in the late 1990s3,4 as the crucial distinguishing feature between mature NK cells and junction between a T cell and an antigen-presenting cell cytotoxic T lymphocytes (CTLs), both of which are (APC) at which T-cell receptors (TCRs) interact with efficient at mediating cytotoxicity. MHC molecules. Subsequent studies extended these NK-cell cytotoxicity involves the secretion of cyto- observations and identified relevant immunological lytic effector molecules from specialized organelles that synapses between different types of immune cell, as University of Pennsylvania are known as lytic granules. Much of what is known well as between immune cells and non-immune cells. School of Medicine, Joseph about this process is derived from studies of CTLs and Thus, an immunological synapse can be defined as the Stokes Jr Research Institute this has provided guidance for subsequent studies of NK orderly rearrangement of molecules in an immune cell of The Children’s Hospital of Philadelphia, 3615 Civic cells. However, there are several important differences at the interface with another cell. Numerous molecules Center Boulevard, ARC between NK cells and CTLs, and so the processes lead- have been identified as participating in the immunologi- 1016H, Philadelphia, ing to cytotoxicity by the two cell types should not be cal synapse, including receptors, signalling molecules, Pennsylvania 19104, USA. assumed to be identical. For example, the lytic granules cytoskeletal elements and cellular organelles. Some stud- e-mail: [email protected]. are preformed in resting human NK cells but not in ies suggest that these molecules accumulate in distinct upenn.edu doi:10.1038/nri2381 CTLs. As a result, the cytolytic process in NK cells needs regions in an activating immunological synapse to form Published online to be well regulated, and this might involve additional a supramolecular activation cluster (SMAC), which may 18 August 2008 or enhanced mechanisms for controlling the secretion be segregated into peripheral (pSMAC) and central NATURE REVIEWS | IMMUNOLOGY VOLUME 8 | SEPTEMBER 2008 | 713 REVIEWS Microclusters (cSMAC) zones. However, the purpose of this molecular Lytic granules are hybrid organelles that are special- Discrete collections patterning is debatable, as functions typically attributed ized for the secretion of the lytic effector molecules of molecules at the to the SMAC can be induced in its absence under some which reside in them (BOX 2). For an NK cell to mediate immunological synapse that circumstances5. Furthermore, single molecule studies cytotoxicity, lytic granules are emptied onto a target can move in the plasma (FIG. 1) membrane and generate and kinetic studies of the immunological synapse have cell at a prototypical mature lytic synapse . In signals. They are smaller than shown that, in some settings, the engagement of indi- the mature synapse, filamentous actin (F-actin) and and exclusive of the central vidual receptors6 or the involvement of microclusters of adhesion receptors accumulate and are thought to supramolecular activation cell-surface and signalling molecules can support cell form a ring in the pSMAC through which perforin and cluster, which can represent activation without the need for a mature synapse7,8. other lytic-granule contents are secreted. Domains in a coalescence of multiple microclusters. Therefore, the importance of larger scale accumulations the lytic synapse that contain specific signalling mol- and distinct segregation of molecules at the synapse is ecules or secretory machinery have been described Perforin currently being re-evaluated. in CTLs9, but may not always be required for CTL- A component of cytolytic 6 Although debate regarding the role of the immuno- mediated cytotoxicity . Similar molecule distribution granules that participates in the permeabilization of plasma logical synapse in enabling immune responses con- patterns have been observed in NK cells, albeit incon- 10–12 membranes, thereby allowing tinues, several of its potential functions seem relevant sistently , and many aspects of NK-cell synapse granzymes and other cytotoxic and worth considering (BOX 1). Many of these functions organization have not been elucidated. However, lytic components to enter or be were originally assigned to the immunological synapse granules are large organelles and must traverse dense taken up by target cells. between a T helper cell and an APC, but they also apply F-actin networks at the synapse, and actin reorganiza- to the NK-cell synapse. Certain aspects, however, are tion is required for their release. Therefore, synapse more relevant to NK cells, such as the directed secretion formation has the specific function in NK cells of of lytic granules for cytotoxicity. enabling cytotoxicity. Box 1 | Proposed functions of the immunological synapse There are numerous functions ascribed to the immunological synapse, many of which are relevant to natural killer (NK) cells. Ligand recognition. The immunological synapse creates a crucial zone where ligands can be recognized accurately by their cognate receptors among many non-relevant ligands. Signal amplification and integration. Whether in large clusters at the central supramolecular activation cluster (cSMAC) or in discrete microclusters that are located in the periphery, important signalling molecules localize with receptors at the synapse. Innovative studies in NK cells have described functional signalling at these sites40, as well as functional integration of signals11. Co-stimulation. Co-stimulatory ligands, such as CD40 ligand116 and OX40L ligand117, that are expressed by NK cells can bind receptors on adaptive immune cells to facilitate immune responses. In vivo, NK cells have been shown to engage with other innate cells and T cells simultaneously118. The innate cell presumably induces the expression of NK-cell co-stimulatory ligands, which are then recognized by adjoining T cells. Cytotoxicity. The close approximation of an NK cell and its target cell that is conferred by the immunological synapse ensures precise targeting of cytotoxicity31 and can protect neighbouring cells from the damaging effects of cytotoxic mediators. Directed secretion. The arrangement of molecules at the synapse can create a conduit through which cellular components can be secreted9. Linkage between the synapse and intracellular transport machinery allows the focused secretion of small and large components, including lytic granules21 and cytokines119. Multidirectional secretion. Activation signals originating from molecules in the synapse can induce secretion at sites away