Post-transcriptional regulation of T cell function by metabolic enzymes
Resting T cells use oxidative phosphorylation to generate energy, and greatly promote aerobic glycolysis upon activation. It was thought that this engagement of aerobic glycolysis was required to meet the metabolic demands of proliferation. However, why proliferating T cells would adopt this less efficient energy metabolism, especially in an oxygen-replete environment, remained incompletely understood.
During the course of our studies we found that aerobic glycolysis is actually required for effector function in T cells, in particular, for optimal production of effector cytokines, but that this pathway is not necessary for their proliferation or survival. We found that this defect in effector function was translational, and regulated by the binding of the glycolysis enzyme GAPDH to AU-rich elements within the 3’ UTR of cytokine mRNA. We demonstrated that GAPDH, by engaging/disengaging glycolysis, controlled cytokine production in a posttranscriptional manner (Figure 3).
One of our future goals is to define how the RNA binding function of metabolic enzymes is altered by the engagement of particular cellular metabolic pathways, and how this ultimately influences T cell function in different conditions in vivo.