Luke Turner (Mentor: Will Bailis, PhD)

“NAD salvage is a metabolic mediator of TCR stimulation dependent T cell function”

Luke Turner, Clémence Quériault, Janet Nguyen, James Davis, Patrick Schaefer, Michael Scaglione, Kelly Rome, Alisa Sukina, Brian Goldspiel, Catherine Michelutti, Joseph Baur and Will Bailis

An activated T cell’s exit from quiescence is initiated by TCR engagement and a series of subsequent signaling cascades that drive cell survival, differentiation, and proliferation programs. Importantly, the strength of these activating signals help dictate clonal selection by determining quality and kinetics of activation. Concurrent to the early signaling and genetic rewiring during T cell activation is a metabolic rewiring which supports the biochemical demands of these processes. We have found that a central component of these early metabolic alterations is a marked expansion of cellular NAD+ levels which are driven by NAD salvage pathway activity. NAD salvage is engaged in activated T cells in a manner proportionate to the strength of TCR stimulation. This proportionate activity is then required to maintain cell cycle entry and progression in a Myc stability dependent mechanism. Conversely, the NADH status of a cell can be used as a predictive tool to determine future cell divisions. The T cell requirement for NAD salvage is dynamic and includes specific windows of requirement which parallel the need for mitochondrial ATP as well as windows for division enhancement potential by NAD+ precursors. Combined, these data illustrate that regulation of NAD+ content through the NAD salvage pathway is a metabolic mechanism in which T cells interpret external signaling cues to set and facilitate their level of activation.