Constitutive Glycolytic Metabolism Supports CD8+ T Cell Effector Memory Differentiation during Viral Infection

Extensive metabolic changes accompany T cell activation, including a switch to glycolytic energy production and increased biosynthesis. Recent studies suggest that subsequent return to reliance on oxidative phosphorylation and increasing spare respiratory capacity are essential for the differentiation of memory CD8+ T cells. In contrast, we found that constitutive glycolytic metabolism and suppression of oxidative phosphorylation in CD8+ T cells, achieved by conditional deletion of hypoxia-inducible factor regulator Vhl, accelerated CD8+ memory cell differentiation during viral infection. Despite sustained glycolysis, CD8+ memory cells emerged that upregulated key memory-associated cytokine receptors and transcription factors and showed a heightened response to secondary challenge. In addition, increased glycolysis not only permitted memory formation, but it also favored the formation of long-lived effector-memory CD8+ T cells. These data redefine the role of cellular metabolism in memory cell differentiation, showing that reliance on glycolytic metabolism does not hinder formation of a protective memory population. •Increased SRC and a reliance on OXPHOS are not essential for memory CD8+ T cells•Glycolytic metabolism does not hinder differentiation of memory CD8+ T cells•Provision of ATP is paramount to metabolic pathway usage in effector T cell responses•Glycolytic metabolism may preferentially promote differentiation of Tem cells Whether alterations in cellular metabolism correlate with or drive CD8+ T cell differentiation is unclear. Phan and colleagues demonstrate that memory T cell differentiation does not require generation of SRC or a switch to reliance on OXPHOS. Furthermore, glycolytic metabolism not only supports memory differentiation but may promote Tem cells.