Project Summary Natural killer (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. NK cells are activated when they detect an imbalance in the signals from receptors on their cell surface, either a loss of inhibitory signals or activation through activating receptors including cytokine receptors. Alterations in these signaling pathways impact the transcriptional regulatory networks that contribute to NK cell activation and effector function. At the present time there is a gap in our knowledge of the major transcription factors that are impacted by these signaling pathways and how they modulate NK cell function. In this R21 application, we present data to support the hypothesis that Batf, the founding member of the AP-1 family of transcription factors, is induced by proinflammatory cytokine signaling in NK cells and impacts multiple aspects of the NK cell response. In aim 1, we will test the hypothesis that Batf regulates key genes involved in NK cell expansion, survival, and effector function by identifying direct Batf targets during the response to mouse cytomegalovirus. In aim 2, we will test the hypothesis that Batf plays unique roles in different NK cell activating contexts by testing the requirement for Batf in the NK cell response to metastatic melanoma and in a solid tumor model that relies on NK cell migration and chemokine production. Taken together, these studies will provide a broad view of the requirements for Batf in distinct NK cell activation contexts and lead to the identification of Batf targets that underlie its essential functions.