The Histone Methyltransferase KMT2D promotes Natural Killer cell effector molecule release

Natural Killer (NK) cells eliminate virally infected and cancerous cells by secreting cytotoxic granules and pro-inflammatory cytokines. However, the epigenetic mechanisms that coordinate these processes in human NK cells remain poorly understood. We identified two NK deficiency (NKD) patients with mutations in the histone methyltransferase KMT2D that demonstrated impaired cytotoxicity and degranulation. CRISPR-mediated KMT2D deletion or introduction of a patient-specific mutation in healthy human NK cells was sufficient to inhibit effector functions. NK cell-specific KMT2D deletion in mice resulted in defective NK cell degranulation and IFN-γ production, increasing mortality following MCMV infection. KMT2D loss reduced H3K4me1 deposition, associated with decreased levels of RAB3D. RAB3D-deficient human NK cells reduced the release of GZMB and IFN-γ, without impacting intracellular levels. Thus, KMT2D acts as a conserved epigenetic regulator of mature NK cell functions, promoting rapid effector molecule release.

Mutations in KMT2D are associated with human NKD.KMT2D is required for NK cell cytotoxicity and degranulation.Loss of KMT2D in mouse NK cells increases susceptibility to MCMV infection.KMT2D regulates RAB3D to enhance the release of effector molecules.