Review Article | Published:

Formation and function of the lytic NK-cell immunological synapse

Nature Reviews Immunology volume 8, pages 713725 (2008) | Download Citation



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.

Key points

  • The immunological synapse can be defined as the orderly rearrangement of molecules in an immune cell at the interface with another cell. In natural killer (NK) cells, the lytic immunological synapse is specialized to facilitate cytotoxic activity against the target cell.

  • The main function of the NK-cell lytic synapse is the coordinated and regulated delivery of diffuse lytic granules to the cell–cell interface, so that their contents may be directionally secreted onto a target cell. Tight regulation of this process may be especially important in NK cells as they can contain abundant lytic granules in the resting state.

  • The NK-cell lytic-synapse formation can be described in three stages — initiation, effector and termination — each consisting of individual steps. The initiation stage establishes a productive interaction between the NK cell and the target cell; the effector stage coordinates the secretion of lytic-granule contents specifically onto the target cell, and the termination stage completes the lysis of the target cell and confers renewed cytolytic capacity on the NK cell.

  • Some steps within the individual stages in the formation and function of the NK-cell synapse are thought to occur in a linear manner. A model is presented in which both known and theoretically sequential cellular events are delineated.

  • There are seven known human genetic diseases that are characterized by defects in specific steps in the formation and function of the NK-cell synapse. Owing to their known molecular pathogenesis, studies of these diseases provide insight into the cell biological processes that facilitate NK-cell lytic-synapse formation. Additional mechanistic understanding of the pathogenesis of the associated clinical phenotype, haematophagocytic lymphohistiocytosis, can also be gained from studying these diseases.

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This work was supported by the US National Institutes of Health (grant AI-067946) and a faculty development award from the Education Research Trust of the American Academy of Allergy, Asthma and Immunology. I thank J. Burkhardt for her comments on the manuscript, and I apologize to the authors of the many relevant works that could not be cited owing to space constraints.

Author information


  1. University of Pennsylvania School of Medicine, Joseph Stokes Jr Research Institute of The Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, ARC 1016H, Philadelphia, Pennsylvania 19104, USA.

    • Jordan S. Orange


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Supplementary information


  1. 1.

    Supplementary information S1 (Figure) | Interactive version of a prototypical mature NK-cell lytic synapse

    The mature natural killer (NK)-cell lytic synapse in FIG. 1 is provided in an interactive format, whereby placing the cursor over the cell and clicking the mouse button allows for the cell to be dragged in different directions for a full 360 degrees of interaction. The image shows a human NK cell (YTS cell line) expressing Cd2–GFP (green fluorescent protein) fusion protein conjugated to a target cell (an Epstein–Barr-virus-transformed B-cell line). NK cells were conjugated to the target cells, fixed, permeabilized and stained with a perforin-specific monoclonal antibody (red) to visualize the lytic granules. The serial images were obtained using confocal microscopy by serial acquisition of optical slices along the z-axis and followed by the three-dimensional reconstruction in silico. QuickTime virtual reality (QTvR) output and Improvision volocity visualization software were used to generate complete rotation of the images around the z-axis. The accumulated GFP fluorescence indicates the supramolecular activation cluster (SMAC) that forms at the synapse between the NK cell and the target cell. Notably, a region in the centre of the SMAC that is devoid of GFP is consistent with the presence of a central SMAC (cSMAC) and delineates a channel through which the secretion of lytic-granule contents is likely to occur. Although there is an accumulation of perforin inside the SMAC (consistent with the lytic granules surrounding the microtubule-organizing centre), perforin can be seen coming from this region to the cSMAC. This is consistent with the secretory domain of the lytic synapse.


'Danger' signals

Agents that alert the immune system to danger and thereby promote the generation of immune responses. Danger signals can be associated with microbial invaders (exogenous danger signals), and can also be produced or expressed by damaged cells (endogenous danger signals).


Discrete collections of molecules at the immunological synapse that can move in the plasma membrane and generate signals. They are smaller than and exclusive of the central supramolecular activation cluster, which can represent a coalescence of multiple microclusters.


A component of cytolytic granules that participates in the permeabilization of plasma membranes, thereby allowing granzymes and other cytotoxic components to enter or be taken up by target cells.

Lipid rafts

Liquid-ordered membrane domains that are enriched in sphingolipids and cholesterol, and also contain glycophosphatidylinositol-anchored receptors. They can provide ordered structure to the lipid bilayer and have the ability to include or exclude specific signalling molecules and complexes. Given that most techniques for studying lipid rafts are indirect (such as cell-membrane binding of cholera toxin, cholesterol sequestration using nonspecific reagents and cell fractionation based on detergent sensitivity), their physiological relevance and function remain controversial.

Microtubule-organizing centre

(MTOC). A structure that is found in all plant and animal cells from which microtubules radiate. The two most important types of MTOC are the basal bodies that are associated with cilia, and the centrosome, which is composed of γ-tubulin-ring complexes for microtubule nucleation.

Vesicle priming

The process of preparing, through the acquisition of biochemical attributes, a secretory vesicle (such as a lytic granule) for fusion with the inner leaflet of the membrane.


(Natural-killer group 2, member D). A primary activating receptor that is encoded by the NK-cell gene complex and is expressed by all mature NK cells. It recognizes distinct families of ligands that are generally expressed only by infected, stressed or transformed cells.

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