Our lab showed that the transcription factor promyelocytic leukemia zinc finger (PLZF, zbtb16) is essential for the development of the effector functions of natural killer T cells (NKT cells). This highly conserved protein is also expressed in human and rat NKT cells. Lymphocytes that express PLZF take on wholly different characteristics and effector functions than non-PLZF expressing lymphocytes; the cells are arguably transformed into a distinct lineage by the expression of this transcription factor. In contrast to mice and rats, we have shown that PLZF is expressed by all human NK cells. Furthermore, we have shown that NK cells from the only known person in the world to have a biallelic loss of function of PLZF have both an altered phenotype and function. We propose that a novel transcription factor network controls the self-regulation of NK cell responses in humans. This network will be studied by the use of primary human NK cells and by the use of PLZF deficient NK cells that we will differentiate from induced pluripotent stem cells that we made from the PLZF deficient person. These studies are of high significance because, although NK cell therapies hold great promise for the treatment of diseases such as cancer, clinical success has been limited. Understanding activation checkpoints will provide targets for enhancing therapeutic NK cell activity.