My research is focused upon human natural killer (NK) cell biology as well as primary immunodeficiencies. NK cells are the major lymphocyte of the innate immune system and function in protection against viral infection and malignancy. Primary immunodeficiencies are naturally-occurring congenital defects of human immunity typically due to single gene mutations. Work in my laboratory is frequently directed at the union of these two fields and how we might learn about NK cell biology from human genetic immunodeficiency. We have defined NK cell defects in several primary immunodeficiencies including Wiskott-Aldrich syndrome, May-Hegglin Anomaly, and NF-κB essential modulator deficiency. These studies have led us to detailed investigations regarding events leading up to NK cell function, namely cytotoxicity, directed against a diseased cell. These functions of the NK cell are contact dependent and require the formation of a lytic immunological synapse, which represents a dynamic molecular organization at the interface with the target cell. We have defined that the lytic immunological synapse is formed and progresses in a series of steps. These culminate with an NK cell secreting the contents of highly specialized organelles, called lytic granules, through the immunological synapse directly onto a target cell. Through study of NK cells from individuals with specific primary immunodeficiencies, we have defined linear checkpoints in immunological synapse formation and function. These have also allowed us to return to the bedside, as in 2009, we initiated a Phase-I clinical trial aimed at reversing defects of the NK cell immunological synapse in a primary immunodeficiency.