Towards understanding the role of nutrient conditions and metabolic modulation in CD4+ T cell activation

Abstract

T-cell activation is a highly regulated process that requires both controlled and metabolic adaptations to support proliferation and effector functions. Upon activation, the induction of autophagy and glycolysis play a crucial role in regulating and driving T-cell tolerance and epigenome reprogramming, respectively. Here, we explore how nutrient deprivation, autophagy and glycolysis inhibition affect T-cell anergy. Preliminary data suggest that activation-induced autophagy occurs independently of ULK1/2, while glycolysis inhibition appears to induce the expression of anergy-associated genes. Additionally, we develop molecular tools to explore the role of the metabolic Pyruvate Dehydrogenase Complex (PDC) in T-cell activation. PDC, which catalyzes the conversion of pyruvate to acetyl-CoA, shows nuclear translocation upon T-cell receptor engagement, implicating it in epigenetic regulation. In HEK293T cells, we present preliminary findings on the specific inhibition of nuclear PDC, the formation of biomolecular condensates, and the nuclear PDC proteome. Our findings highlight a metabolic and epigenetic interplay during T-cell activation.