Role of DOCK8 in cytokine storm syndromes.

backgroundCytokine storm syndromes (CSSs), including hemophagocytic lymphohistiocytosis (HLH), are increasingly recognized as hyperinflammatory states leading to multiorgan failure and death. Familial HLH in infancy results from homozygous genetic defects in perforin-mediated cytolysis by CD8 T lymphocytes and natural killer (NK) cells. Later-onset CSSs are often associated with heterozygous defects in familial HLH genes, but genetic etiologies for most are unknown. We identified rare dedicator of cytokinesis 8 (DOCK8) variants in patients with CSS.

objectiveWe sought to explore the role of CSS patient-derived DOCK8 mutations on cytolytic activity in NK cells and to further study effects of DOCK8 deficiency in murine models of CSSs.

methodsDOCK8 cDNAs from 2 unrelated patients with CSS with different missense mutations were introduced into human NK-92 cells by foamy virus transduction. NK-cell degranulation (CD107a), cytolytic activity against K562 target cells, and IFN-γ production were explored by flow cytometry. A third patient with CSS with DOCK8 mRNA splice acceptor site variant was explored by exon trapping. Dock8

resultsBoth patient DOCK8 missense mutations decreased cytolytic function in NK cells in a partial dominant-negative fashion in vitro. The patient DOCK8 splice variant disrupted mRNA splicing in vitro. Lymphocytic choriomeningitis virus infection promoted CSS in Dock8

conclusionsMutations in DOCK8 may contribute to CSS-like hyperinflammatory states by altering cytolytic function in a threshold model of disease.