Impaired metabolic reprograming in antigen-activated recent thymic emigrants

Abstract

Abstract Recent thymic emigrants (RTEs) are the youngest peripheral T cells that have completed thymic selection and egress to the lymphoid periphery. However, T cell maturation does not end in the thymus; rather, RTEs require 2 – 3 weeks in the lymphoid periphery to achieve functional maturity and enter the mature but naïve (MN) T cell pool. Following antigen encounter, RTEs are functionally distinct from MN T cells as they exhibit dampened proliferation, altered cytokine production, and increased expression of some anergy-associated genes. RTEs are a clinically important population as these cells contribute significantly to the T cell pool in neonates and adults recovering from HIV infection or chemotherapy. Here we show that, compared to MN T cells, RTEs are impaired in their ability to switch from oxidative phosphorylation to aerobic glycolysis following antigenic stimulation. This impaired metabolic reprograming contributes to the reduced proliferation and cytokine production observed in antigen-activated RTEs. This failure to undergo antigen-induced metabolic reprograming is associated with reduced expression of the transcription factor Myc. Critically, high levels of IL-2 are able to rescue the expression of Myc in RTEs resulting in proper metabolic reprograming that mimics their mature counterparts. These results suggest that an altered metabolic phenotype underlies the functional differences observed between RTEs and MN T cells and highlights a novel point for therapeutic intervention for neonates and individuals recovering from lymphoablation.