Investigating immune cell metabolism (immunometabolism) in T cell biology, systems immunology and human disease
How does a T cell know that it’s a T cell? How does a T cell know what to do to protect us from infection and disease? Read how scientists at St. Jude are unraveling the complex biology behind these processes. #StJudeOn
Cellular metabolism is connected both to the immune response and diseases like cancer. Our laboratory seeks to understand how these connections work by using systems biology tools and interdisciplinary strategies. Through our work, we hope to gain new insights into disease mechanisms and potential therapeutic targets.
Metabolism is the core process underlying all biological functions. Our goals are to discover the mechanisms linking the metabolic state of immune cells (immunometabolism) with tissue homeostasis and function, and to use these insights for better treatments for cancer and other diseases. We are particularly interested in understanding the metabolic programs (e.g. glucose, lipid, and mitochondrial metabolism), signaling pathways (e.g. mTOR and Hippo kinases; metabolite- and nutrient-induced signaling), and systems-level regulatory networks (e.g. interactions between protein regulators and their targets) in basic T cell and dendritic cell biology and antitumor immunity. To gain an integrative view, we combine the traditional hypothesis-driven approach with systems biology principles, including data-driven network algorithms, in vivo functional screening and systems proteomics, to identify new concepts and hidden drivers for immunometabolism that cannot be surmised from simpler systems. Our research program addresses three fundamental questions in immunometabolism:
Our work has contributed to the current understanding of the principles of metabolic reprogramming for T cell state (e.g. T cell quiescence and quiescence exit), T cell fate (the differentiation and heterogeneity of T cell subsets), and immune tolerance mediated by regulatory T cells. We are currently applying in vivo CRISPR screening, hidden driver analysis, and single-cell biology to understand metabolic pathways and drivers in T cell fate specification and tissue adaptation.
We have identified how nutrient cues, such as those from the environment or the process of autophagy, serve as potent regulators of cellular metabolism, and how dendritic cell-derived immune and metabolic signals are integrated by T cells. We are currently exploring immune cell-context-specific nutrient signaling networks (e.g. transporters and sensors), and combining systems proteomics (e.g. protein-protein-interaction network) and functional genomics (e.g. CRISPR screening) approaches to build nutrient-sensitive signaling roadmaps.
Capitalizing on the remarkable expertise of St. Jude in pediatric cancer, we use systems immunology strategies to identify new disease targets in pediatric immuno-oncology by exploiting the metabolic barriers to immunity and disease. This new frontier in our research program involves extensive collaborative efforts, exemplified by a new interdisciplinary initiative to identify innovative immuno-oncology targets in pediatric cancer known as the iTARGETS (Immuno-Oncology Target Identification via Systems Immunology) “blue sky” project.
Together, by integrating hypothesis-driven and systems immunology approaches, we aim to establish fundamental insights into immunometabolism and discover the mechanisms and targets that connect metabolic programs to immunity and disease.