Mutations in the DOCK8 gene cause an autosomal recessive form of hyper-immunoglobulin E syndrome, characterised by chronic immunodeficiency with persistent microbial infection and increased incidence of malignancy. These manifestations suggest a defect in cytotoxic lymphocyte function and immune surveillance. However, how DOCK8 regulates NK cell-driven immune responses remains unclear. Here, we demonstrate that DOCK8 regulates NK cell cytotoxicity and cytokine production in response to target cell engagement or receptor ligation. Genetic ablation of DOCK8 in human NK cells attenuated cytokine transcription and secretion through inhibition of Src family kinase activation, particularly Lck, downstream of target cell engagement or NKp30 ligation. PMA/Ionomycin treatment of DOCK8 deficient NK cells rescued cytokine production, indicating a defect proximal to receptor ligation. Importantly, NK cells from DOCK8 deficient patients had attenuated production of IFN and TNF upon NKp30 stimulation. Taken together, we reveal a novel molecular mechanism by which DOCK8 regulates NK cell driven immunity. SOURCE: Conor Kearney (conor.kearney@petermac.org) -  Peter MacCallum cancer Centre

Pluto Bioinformatics

GSE101467: Gene expression in control and DOCK8 CRISPR KHYG1 NK cells