In this project, we propose to explore a new area in biological research aiming at dissecting emerging of properties of the innate immune responses. Our system model is the Natural Killer (NK) cell. Specifically, we will investigate the mechanisms by which these players of innate immunity achieve tolerance to self and participate to immune responses. Multidisciplinary approaches will be combined to achieve groundbreaking results at nanoscopic and macroscopic scales on the following issues:- How NK cells are educated to self-tolerance?- How NK cells distinguish their targets from normal cells?- How NK cells participate to immunological memory?THINK (THe Immune function of Natural Killer cells) is a challenging project supported by an array of preliminary data obtained by our team of investigators in various fields of expertise:- innate immunity and NK cells in human and mouse models- random insertional mutagenesis in the mouse- genome-wide epigenetic, transcriptomic and RNAi analysis and- state-of-the-art optical imaging techniques from intravital biphoton microscopy to the quantification of proteins in nano-sized areas of the cell.THINK is thus a multidisciplinary project that bridges disciplines: immunology, biophysics, genetics and epigenetics. In a scientific perspective, we think that this project will open new technological and scholar horizons, in reassessing the actual concepts on the links between innate immunity, tissue homeostasis and stress response. In a clinical and translational perspective, we also think that this project will help to design innovative NK cell-based therapies and immunomonitoring protocols.