Project Summary NK cells play essential roles in the immune response to intracellular pathogens, including viruses and bacteria, and form an important defense against malignant transformation and metastasis. In this R21 application, we propose experiments to test the hypotheses that the transcription factor Helios is a central regulator of undifferentiated NK cells, supporting their self- rewak and limiting effector maturation. We present evidence that Helios is expressed in the most undifferentiated of mature NK cells and up-regulated in Ets1-deficient NK cells, which fail to mature appropriately and have multiple defects in NK cell receptor expression and function. We will create mice lacking Helios, or Ets1 and Helios, in NK cells to determine whether these cells show premature effector maturation and altered response to cytokines, tumor cells (melanoma) or virus (mouse cytomegalovirus). Our studies will provide a foundation for understand the mechanisms underlying NK cell self-renewal effector maturation.