Abstract
Natural killer (NK) cells are lymphocytes of the innate immune system that secrete cytokines upon activation and mediate the killing of tumor cells and virus-infected cells, especially those that escape the adaptive T cell response caused by the down regulation of MHC-I. The induction of cytotoxicity requires that NK cells contact target cells through adhesion receptors, and initiate activation signaling leading to increased adhesion and accumulation of F-actin at the NK cell cytotoxic synapse. Concurrently, lytic granules undergo minus-end directed movement and accumulate at the microtubule-organizing center through the interaction with microtubule motor proteins, followed by polarization of the lethal cargo toward the target cell. Ultimately, myosin-dependent movement of the lytic granules toward the NK cell plasma membrane through F-actin channels, along with soluble N-ethylmaleimide-sensitive factor attachment protein receptor-dependent fusion, promotes the release of the lytic granule contents into the cleft between the NK cell and target cell resulting in target cell killing. Herein, we will discuss several disease-causing mutations in primary immunodeficiency syndromes and how they impact NK cell-mediated killing by disrupting distinct steps of this tightly regulated process.
Highlights
Natural killer (NK) cells comprise 5–15% of human peripheral blood lymphocytes and play an important role in the clearance of virally infected cells, as well as the elimination of cancer cells [1, 2]
The IL-2-mediated rescue of the defect in Wiskott–Aldrich syndrome (WAS) NK cells was found to be independent of WAS protein (WASP) function, but dependent on another WASP family member, WAVE2 [141]. These findings suggest that there exists two distinct pathways for Arp2/3-generated F-actin reorganization at the cytotoxic synapse (CS) in NK cells, and future studies should enable the use of IL-2 as a therapy to improve clinical symptoms of WAS including severe herpes simplex virus (HSV) infection caused by defective NK cell-mediated cytotoxicity
Advances in clinical diagnostics has substantially increased the identification of patients with primary immunodeficiency syndromes (PIDs) that affect NK cell numbers or effector functions
Summary
Natural killer (NK) cells comprise 5–15% of human peripheral blood lymphocytes and play an important role in the clearance of virally infected cells, as well as the elimination of cancer cells [1, 2]. Research conducted over the past quarter of a century has uncovered the process of NK cell development, identified and demonstrated the function of activating and inhibitory receptors, and provided a wealth of information regarding the signaling pathways that are linked to these receptors and the proteins that are critical to the delivery of the lethal cargo to the target cell. The study of human primary immunodeficiency syndromes (PIDs) has provided invaluable knowledge and insight regarding the role of NK cells in the immune system, and in addition has resulted in the identification of genes whose protein products regulate distinct steps that are critical to the development of cellular cytotoxicity by this population of innate immune cells. The term NK cell deficiency does not just mean an absence of NK cells in the immune system; it includes the absence of specific NK cell effector functions, like cytotoxicity, despite the www.frontiersin.org
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