Investigating Amino Acid Regulation in T cells

Abstract

Amino acids are fundamental to cellular homeostasis and have emerged as critical regulators of T cell activation, differentiation, and effector function. Despite their importance, the specific requirements and temporal dynamics of amino acid utilization in distinct T cell subsets remain incompletely understood. This dissertation investigates how modulation of amino acid availability and transporter function influences CD4⁺ and CD8⁺ T cell responses in contexts of autoimmunity and tumor immunity. In CD4⁺ T cells, we identify asparagine as a conditionally essential amino acid, necessary for optimal activation, proliferation, and differentiation. Asparagine depletion impaired these processes in vitro and attenuated disease severity in a mouse model of experimental autoimmune encephalomyelitis, highlighting its potential as a therapeutic target. In CD8⁺ T cells, we uncover a regulatory role for the amino acid exporter Slc43a2. Genetic ablation of Slc43a2 enhances T cell activation, effector function, and proliferation in vitro and promotes tumor control in vivo. These findings suggest that Slc43a2 limits nutrient acquisition and metabolic fitness during T cell activation. Together, this work demonstrates how manipulation of amino acid availability and transport can differentially modulate T cell subsets and presents novel strategies for immunotherapeutic intervention.