Grant: Project Grant

Natural Killer (NK) cells are named for their remarkable ability to swiftly recognize and eliminate cells that pose a threat to the body, such as virus-infected cells or healthy cells that have turned cancerous. However, this immense power comes with the risk of causing tissue damage or autoimmunity. To prevent such harm, the body employs safeguard mechanisms to regulate NK cells. For instance, when NK cells are activated for prolonged periods, they naturally become less functional. This ensures that if they begin to promote harmful responses, they do not constitute a significant danger to the body. Despite their importance, the biological mechanisms that govern NK cell dysfunction and regulation remain poorly understood. Tumors can exploit these regulatory mechanisms to evade NK cell-mediated destruction, complicating efforts to restore NK cells' anti-cancer capabilities. In this application, we aim to investigate the molecular mechanisms driving NK cell dysfunction. We hypothesize that persistent stimulation leads to a loss of NK cell functionality because the cellular machinery required to sustain their responsiveness becomes less available to other cellular components. To test this, we will utilize a platform that accurately replicates key aspects of the process by which NK cells lose function. Through these experiments, we will clarify how NK cells become dysfunctional and how this knowledge can be leveraged for pre-clinical and clinical applications. Understanding how NK cells are regulated will not only provide insights into a biologically intriguing process but also inform the development of new therapies to rejuvenate NK cells' ability to fight cancer and infectious diseases.