The Histone Methyltransferase KMT2D promotes Natural Killer cell effector molecule release

Natural Killer (NK) cells play a crucial role in eliminating virally infected and cancerous cells by releasing cytotoxic granules and pro-inflammatory cytokines. The epigenetic mechanisms that control these functions in human NK cells have not been well understood until now. Researchers identified two NK deficiency (NKD) patients carrying mutations in the histone methyltransferase KMT2D, which led to impaired cytotoxicity and degranulation.

By using CRISPR technology, they were able to confirm that deleting or introducing a patient-specific mutation of KMT2D in healthy human NK cells inhibited their effector functions.

To further investigate the role of KMT2D, researchers performed NK cell-specific KMT2D deletion in mice. This resulted in defective NK cell degranulation and IFN-γ production, leading to increased mortality following MCMV infection. The study also found that KMT2D loss reduced H3K4me1 deposition, which was associated with decreased levels of RAB3D.

When human NK cells lacking RAB3D were examined, it was discovered that these cells released fewer GZMB and IFN-γ molecules, despite having normal intracellular levels. The findings indicate that KMT2D acts as a conserved epigenetic regulator of mature NK cell functions, promoting rapid effector molecule release.