Glycolysis determines dichotomous regulation of T cell subsets in hypoxia

Hypoxia occurs in many pathological conditions, including chronic inflammation and tumors, and is considered to be an inhibitor of T cell function. However, robust T cell responses occur at many hypoxic inflammatory sites, suggesting that functions of some subsets are stimulated under low oxygen conditions. Here, we investigated how hypoxic conditions influence human T cell functions and found that, in contrast to naive and central memory T cells (T-N and T-CM), hypoxia enhances the proliferation, viability, and cytotoxic action of effector memory T cells (T-EM). Enhanced TEM expansion in hypoxia corresponded to high hypoxia-inducible factor 1 alpha (HIF1 alpha) expression and glycolytic activity compared with that observed in T-N and T-CM. We determined that the glycolytic enzyme GAPDH negatively regulates HIF1A expression by binding to adenylate-uridylate-rich elements in the 3'-UTR region of HIF1A mRNA in glycolytically inactive T-N and T-CM. Conversely, active glycolysis with decreased GAPDH availability in T-EM resulted in elevated HIF1 alpha expression. Furthermore, GAPDH overexpression reduced HIF1 alpha expression and impaired proliferation and survival of T cells in hypoxia, indicating that high glycolytic metabolism drives increases in HIF1 alpha to enhance T-EM function during hypoxia. This work demonstrates that glycolytic metabolism regulates the translation of HIF1A to determine T cell responses to hypoxia and implicates GAPDH as a potential mechanism for controlling T cell function in peripheral tissue.