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.