Michael Scaglione (Mentor: Will Bailis)

“Uncovering mechanisms of nutrient-sensitive gene regulation in T lymphocytes”

Michael Scaglione, Kelly Rome, Crystal Conn, Will Bailis

All cells have evolved ways of gaining information about the metabolic environment and using it to inform changes in gene expression to promote homeostasis or cell-specific functions. T lymphocytes are particularly sensitive to their nutrient environment and alterations in nutrient uptake or utilization have potent effects on T cell fate and function. However, the mechanisms directly linking changes in metabolic environment to control of T cell functional gene expression are incompletely understood. Preliminary data I have collected show that the expression of a wide variety of genes associated with T cell function (including cytokines, cytotoxic molecules, transcription factors, and metabolic enzymes) is distinctly sensitive to the cell’s nutrient environment. Using acute nutrient deprivation as a model, I have revealed that many functional genes are differentially sensitive to acute levels of glucose, glutamine, and other amino acids, with each nutrient having distinct effects as to which gene products are induced or repressed over time. I hypothesize that T cells directly sense levels of these nutrients or their downstream metabolic products and utilize nutrient-sensitive mechanisms of transcriptional, post-transcriptional, and translational gene regulation to acutely govern gene expression in response to changes in nutrient environment. Using targeted and untargeted approaches, my goal is to understand:

  1. which genes in the global T cell transcriptome are acutely sensitive to nutrient levels
  2. which molecular features grant a given gene product sensitivity to nutrient-mediated regulation.
  3. which molecular mechanisms cells utilize to sense nutrient levels upstream (sensors) and directly enforce changes in gene expression (effectors). 

Better understanding of these mechanisms will not only provide basic insight into how T cell function is regulated by metabolism but may also be utilized to promote T cell function in metabolically challenging sites such as tumors during anti-cancer immune responses.