Investigating Metabolic Regulation of CD8+ T Cells: Acylcarnitine-Mediated Dysfunction and Activation-Induced Oxidative Dynamics

Abstract

CD8+ T cells are critical mediators of adaptive immunity. Successful effector responses require coordination between metabolic adaptations, such as increased glycolysis and fatty acid synthesis, epigenetic remodeling, and tightly regulated reactive oxygen species (ROS). While extensive work has examined the role of glucose and glutamine availability in T cell function, the impact of extracellular lipids and distinct lipid species on CD8+ T cell activation remains less well defined. Similarly, although proximal signal transduction has been well-characterized, the integration of activation signals with metabolic and redox states remains incompletely understood. This dissertation seeks to address two related questions. First, we investigate how changes in nutrient availability, specifically increases in fatty acid oxidation (FAO) metabolites associated with metabolic disorder and obesity, suppress CD8+ T cell activation and function. Second, we examine how activation signals remodel the cysteine oxidation landscape of CD8+ T cells to identify key proteins and pathways regulated by oxidative modifications during activation. We demonstrate that long-chain acylcarnitines (LCACs) suppress CD8+ T cell cytokine production and effector function by disrupting the Kennedy pathway and that supplementation with Kennedy pathway intermediates partially rescues this functional impairment. We further identify dynamic, time-dependent changes in cysteine oxidation of proteins involved in T cell receptor signaling, glucose metabolism, and RNA processing during CD8+ T cell activation. Together, this work establishes lipid-driven metabolic disruption and activation-induced cysteine oxidation as key regulatory mechanisms for CD8+ T cell function.