Exploring undefined roles of Calcineurin in restriction of autophagy-mediated TCF-1 degradation in CD8+ T cells

About This Grant

Project Summary Cytotoxic CD8+ T cells confer adaptive immune protection against viruses, intracellular pathogens, and cancer. Efficient CD8+ T cell immunity depends on regulation of a specific set of transcription factors as well as global cellular activity, including nutrient metabolism. We have found in our preliminary study that the activity of the TCR-induced phosphatase Calcineurin is essential for protection of the transcription factor TCF-1, which is critical for immunological memory, and for reprogramming amino acid metabolism for increase biogenesis in highly proliferative T cells through suppression of the catabolic process known as autophagy. Despite the importance of TCF-1 in immunological memory and durable T cell response and the demand for metabolic reprogramming, regulatory mechanisms by which T cells respond to antigens and inflammation and establish highly controlled states are not largely unknown. We initially found that inhibition of Calcineurin by the immunosuppressant Cyclosporin A promotes TCF-1 degradation through autophagy, and our additional experiments have suggested that Calcineurin is the central player that globally restricts the engagement of autophagy in activated T cells exposed to inflammatory cues, which not only leads to protection of TCF-1 but also governs amino acid and protein metabolism during T cell immune responses. In this proposed study, we will conduct multi-angled mechanistic analyses of the actions of Calcineurin in cytotoxic T cells to define the unexplored roles of this phosphatase. Given that Cyclosporin A and its related drug, FK-506, have been broadly used as immunosuppressants in patients undergoing organ transplantation and treatment of autoimmunity, expected findings from this study will provide new insights into T cell biology and into altered immunity in patients with pharmacological immune suppression.