Novel structural and functional insights into T cell metabolism in healthy and disease states

About This Grant

PROJECT SUMMARY T cell mitochondrial metabolism is essential for immune cell functions, including immune surveillance and pathogen neutralization. Conversely, impaired mitochondrial function disrupts T cell activity, often resulting in autoimmune diseases, immunodeficiencies, or malignancies. Yet, our understanding of T cell metabolism and its roles in immunologic diseases is poorly understood. Recent work has provided key clues: 1) Disturbances to immune cell metabolic function often result in disease at two opposing ends of the spectrum: cancer and autoimmunity. 2) Rescue of diseased T cell metabolism restores endogenous T cell function, mitigating both cancer and autoimmunity. Moreover, mitochondrial structure and function are intrinsically linked where respiratory complexes do not function in isolation within mitochondria. Rather, these complexes are organized into higher-order assemblies that are concentrated within the cristae and arranged into multi-complex associations of predefined composition, termed supercomplexes. Different disease states not only disrupt the structures of individual complexes but may also alter supercomplex organization to produce symptomatic mitochondrial bioenergetic dysfunction. However, supercomplex formation has never been directly visualized or measured in T cells. I have developed new approaches to directly visualize 3-dimensional mitochondrial structures in healthy and diseased states in patient and animal cells via in situ cryo-electron tomography (cryo- ET). Using biochemical and cryo-ET studies, my goal is to identify the underlying metabolic changes in T cell mitochondrial structure and function during healthy and disease states. I hypothesize: 1) T cell stimulation results in direct structural changes to the respiratory complexes and their higher order organization into supercomplexes; 2) distinct changes in T cell respiratory complex structures contribute to pathologic metabolic dysfunction. To test this, I will identify T cell physiologic mitochondrial ultrastructure and supercomplex stoichiometry (Aim 1) and identify the contributions of T cell mitochondrial ultrastructure and supercomplex stoichiometry within a melanoma tumor microenvironment (Aim 2). Overall, my work will detail how respiratory complexes and their supercomplex organization are regulated in T cells in health and malignancy for the first time. This work may provide a better understanding of T cell pathology, resulting in more effective structure-guided therapeutic interventions. These studies also provide me with training in immunology, biochemistry, and structural biology critical for my development as a physician-scientist.