Defective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency

Abstract

Introduction DOCK8 mutations are responsible for a rare primary combined immunodeficiency syndrome associated with severe cutaneous viral infections, elevated IgE, autoimmunity, and malignancy. Natural killer (NK) cells are essential for tumor surveillance and defense against virally infected cells. NK cell function relies on Wiskott-Aldrich syndrome protein (WASp) for filamentous actin (F-actin) accumulation at the lytic NK cell immunologic synapse (IS). DOCK8 activates Cdc42, which, together with WASp, coordinates F-actin reorganization. While abnormalities in T and B cell function have been described in DOCK8-deficient patients, the role of NK cells in this disease is unclear. Objectives Understand the role of DOCK8 in NK cell function in order to determine if NK cell abnormalities explain the pathogenesis of the clinical syndrome of DOCK8 deficiency. Methods A cohort of DOCK8-deficient patients was assembled and patient NK cells as well as NK cell lines with stably reduced DOCK8 expression were studied. NK cell cytotoxicity, F-actin content, and lytic immunological synapse formation were measured. Results DOCK8-deficient patient NK cells and DOCK8 knockdown cell lines all had decreased NK cell cytotoxicity, which could not be restored after IL-2 stimulation. Importantly, DOCK8 deficiency impaired F-actin accumulation at the lytic immunological synapse without affecting overall NK cell F-actin content. Conclusions DOCK8 deficiency results in severely impaired NK cell function owing to an inability to form a mature lytic IS via targeted synaptic F-actin accumulation. This defect may underlie and explain important attributes of the DOCK8 deficiency clinical syndrome including the unusual susceptibility to viral infection and malignancy.

Impaired natural killer cell functions in patients with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations

“…[29][30][31] Interestingly, in these conditions addition of IL-2 restores NK cytotoxicity, suggesting that the cell response to IL-2 was preserved in patients with these conditions. 31,32 In contrast, NK cytolytic activity against the susceptible human erythroleukemia K562 cell line was reduced in NK cells activated with IL-2 in patients with STAT1 GOF mutations.…”

Inherited DOCK2 Deficiency in Patients with Early-Onset Invasive Infections

“…When comparing DOCK2- and DOCK8-deficient patients, similarities but also important differences emerge. Both conditions are characterized by recurrent bacterial and viral infections 36 , associated with T-cell lymphopenia 36 , defective NK-cell function 37 , aberrant NKT-cell survival and function 38 , and impaired antibody responses 39 . However, the natural course of DOCK2 deficiency appears to be more severe than that of DOCK8 deficiency.…”

DOCK8 enforces immunological tolerance by promoting IL-2 signaling and immune synapse formation in Tregs

“…DOCK8 regulates actin cytoskeleton-dependent functions in T cells, B cells, NK cells, and DCs (14)(15)(16)(17)(18). DOCK8 deficiency in humans is caused by biallelic mutations in DOCK8 that abolish protein expression (19).…”