Elucidating Mechanisms of Mitochondrial Biogenesis in T Cell Immunity - Project Summary. Despite advances in immunotherapies, understanding the metabolic needs of our adaptive immune system is crucial for effective tumor control. When T lymphocytes encounter tumor antigens, they transition from a naive to an activated state. This activation necessitates a coordinated initiation of the mitochondrial biogenesis program, essential for anabolic growth and anti-tumor activity. However, the exact mechanism by which the T-cell receptor regulates this mitochondrial program remains unclear. To identify genetic regulators of mitochondrial biogenesis, I conducted a hierarchical clustering analysis to uncover patterns of gene expression during the early stages of T-cell activation. Intriguingly, this analysis revealed that the canonical pathway known for orchestrating mitochondrial biogenesis seen in oxidative tissues is absent in T cells. Instead, there was a marked upregulation of a gene called PPARG Related Coactivator 1 (PPRC1). The biological function of PPRC1 and its tissue-specific roles in mitochondrial biology are poorly understood, largely because mice with a whole-body knockout of the Pprc1 allele die post-implantation. Human PPRC1 has low sequence homology (only 12.4%) with PGC-1α and lacks the transcriptional repression motif, suggesting a distinct mode of action. Given these findings and their implications for T-cell immunity, I hypothesize that PPRC1 plays an essential role in driving a unique transcriptional program necessary for mitochondrial biogenesis to regulate T cell differentiation and anti-tumor function. To test this hypothesis, we have generated T cell-specific Pprc1 KO mouse models. In Aim 1 of the proposal, we will examine the fundamental yet largely unknown role of PPRC1 in regulating mitochondrial mass and metabolism in T cells. This aim will identify the transcriptional targets of PPRC1 and elucidate how early TCR ligation induces PPRC1 expression. Aim 2 will define the role of PPRC1 in T cell development, maintenance, and anti-tumor immunity in vivo. Overall, these studies have profound implications in cancer immunology and will challenge the existing paradigm of the mitochondrial biogenesis program during T cell activation. They promise to yield novel approaches to modulate mitochondrial function to enhance anti-tumor immunity. Candidate. Dr. Kiran Kurmi, Ph.D., is the Principal Investigator for this research proposal. As a postdoctoral fellow at Harvard Medical School, he developed tools to study mitochondrial biology and the metabolic needs of T cells. He has secured a tenure-track position for the fall of 2024 and has mapped out a detailed professional development plan to facilitate his transition to an independent researcher. His rigorous training in cancer biology and immunology, combined with his expertise in mass spectrometry and bioinformatics, uniquely positions him to establish an innovative research program examining how mitochondrial mechanisms influence T cell functions and tumor growth. In the long term, he aims to build a solid framework to explore the prevalence of novel metabolite-protein interactions in T cell biology, marking a research path distinct from that of his past mentors.
