Abstract
Natural killer (NK) cells form a subset of lymphocytes that play a key role in immuno-surveillance and host defense against cancer and viral infections. They recognize stressed cells through a variety of germline-encoded activating cell surface receptors and utilize their cytotoxic ability to eliminate abnormal cells. Killing of target cells is a complex, multi-stage process that concludes in the directed secretion of lytic granules, containing perforin and granzymes, at the immunological synapse. Upon delivery to a target cell, perforin mediates generation of pores in membranes of target cells, allowing granzymes to access target cell cytoplasm and induce apoptosis. Therefore, lytic granules of NK cells are indispensable for normal NK cell cytolytic function. Indeed, defects in lytic granule secretion lead or are related to serious and often fatal diseases, such as familial hemophagocytic lymphohistiocytosis (FHL) type 2–5 or Griscelli syndrome type 2. A number of reports highlight the role of several proteins involved in lytic granule release and NK cell-mediated killing of tumor cells. This review focuses on lytic granules of human NK cells and the advancements in understanding the mechanisms controlling their exocytosis.
Highlights
Natural killer (NK) cells form a subset of lymphocytes that play a key role in immuno-surveillance and host defense against cancer and viral infections
The activating receptors CD16, NKG2C/CD94, or natural cytotoxicity receptors NKp30, NKp44, and NKp46 interact with immunoreceptor tyrosinebased activating motif (ITAM)-bearing polypeptides (i.e., CD3ζ, DAP12, FcRγ), while other receptors, such as NKG2D or 2B4, bind to non-ITAM-bearing proteins (e.g., DAP10, SAP) (Chiesa et al, 2005; Lanier, 2005; Bryceson et al, 2006a)
The immunological synapse is defined as a contact between two cells, at least one of them being the immune system cell (e.g., NK cell), that results in the segregation of proteins at the cell-cell interface into micrometer-scale three-dimensional domains (Davis, 2002; Krzewski and Strominger, 2008; Orange, 2008)
Summary
Natural killer (NK) cells form a subset of lymphocytes that play a key role in immuno-surveillance and host defense against cancer and viral infections They recognize stressed cells through a variety of germline-encoded activating cell surface receptors and utilize their cytotoxic ability to eliminate abnormal cells. NK cells express a variety of germline-encoded inhibitory or activating cell surface receptors [reviewed in detail in (Chiesa et al, 2005; Lanier, 2005; Watzl and Urlaub, 2012)]. The number of inhibitory receptors as well as the density of their ligands on the cell surface is sufficient to maximally engage inhibitory receptors (Almeida and Davis, 2006; Endt et al, 2007). A unique feature of human NK cells is the fact, that depending on the target cell www.frontiersin.org
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