Human immunodeficiency syndromes affecting human natural killer cell cytolytic activity

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.

Keywords: NK cell cytotoxicity; NK cells; cytotoxic lymphocytes; cytotoxic synapse; lytic granules; primary immunodeficiency.

Figure 1

Regulation of NK – target cell adhesion and generation of F-actin at the cytotoxic synapse. Initial signals from the NK – target interaction recruit multiple proteins responsible for integrin-mediated adhesion and high affinity maturation as well as the accumulation of F-actin at the cytotoxic synapse (CS). Absence of either the integrin β2-subunit (CD18) or its regulator, Kindlin-3, results in leukocyte adhesion deficiency type I or type III, respectively. NK cells from both diseases present defective cytotoxicity due to failure of efficient target binding and/or defective NK cell activation. The DOCK8–WASP complex is also recruited to the NK-target interface, and a “DOCK8–CDC42– WASP” pathway is likely responsible for F-actin reorganization, which might facilitate integrin-mediated adhesion and provide the F-actin meshwork critical for organization of the CS. Absence of either DOCK8 or WASP results in primary immunodeficiency disorders and NK cells from these patients show impaired NK cytotoxic activity (see text for details).

Figure 2

Fusion and exocytosis of lytic granules during NK cell-mediated cytotoxicity. Directed release of lytic granules toward bound target cells is a multi-step process: (1) lytic granules are rapidly clustered around the MTOC. This retrograde (minus-end-directed) movement along the microtubules occurs rapidly and is mediated by the dynein/dynactin motor complex. (2) The MTOC, along with accumulated lytic granules, are polarized toward the CS, and several proteins have been identified to be critical for this step. (3) Polarized lytic granules are further delivered toward the CS along the microtubule (anterograde transport) in a kinesin-1-dependent manner. (4) Myosin IIA facilitates the final transit of the lytic granules through the hypodense F-actin meshwork at the CS. NK cells from patients with MYH9-related diseases fail to degranulate. (5) The final fusion of lytic granules with the plasma membrane occurs in an orchestrated manner and requires multiple molecules including Rab27a, its effector protein Munc13-4, SNARE proteins, and their accessory proteins. Mutations in proteins involved in this final fusion step have been found to cause immunodeficiency disorders including Griscelli syndrome type 2, familial hemophagocytic lymphohistiocytosis types 3, 4, and 5, all of which have similar clinical symptoms, and defective lytic granule exocytosis.