Nbeal2 is required for neutrophil and NK cell function, and pathogen defence

Mutations in the human NBEAL2 gene cause gray platelet syndrome (GPS), a bleeding diathesis characterised by lack of alpha granules in platelets. The functions of the Nbeal2/NBEAL2 protein have not been explored outside platelet biology, but there are reports of increased frequency of infection and of abnormal neutrophil morphology in GPS patients. We investigated whether there was a role for Nbeal2 in immunity by analysing the phenotype of Nbeal2-deficient mice. We found profound abnormalities in the Nbeal2-deficient immune system, particularly in the function of neutrophils and NK cells. Phenotyping of Nbeal2-deficient neutrophils showed a severe reduction in granule contents across all granule subsets. Despite this, Nbeal2-deficient neutrophils exhibited an enhanced phagocyte respiratory burst relative to Nbeal2+/+, associated with increased expression of cytosolic components of the NADPH oxidase complex. Nbeal2-deficient NK cells were also dysfunctional and showed reduced degranulation. These abnormalities were associated with increased susceptibility to both bacterial (Staphylococcus aureus) and viral (murine cytomegalovirus) infection in vivo. These results define a novel and essential role for Nbeal2 in mammalian immunity.