Formation and function of the lytic NK-cell immunological synapse

Abstract

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.