Bachem et al. showed that microbial production of short-chain fatty acids (SCFAs), specifically butyrate, rewired metabolism in antigen-activated CD8+ T cells by uncoupling oxidative phosphorylation from glycolysis, allowing for enhanced glycolysis and preferential fueling of oxidative phosphorylation through increased glutamine utilization and fatty acid catabolism. These metabolic adaptations promoted CD8+ T cells to transition to a memory phenotype, supporting long-term persistence and enhanced recall responses upon antigen re-encounter. This effect was partially dependent on T cell expression of SCFA receptors GPR41 and GPR43.
Interactions with the microbiota influence many aspects of immunity, including immune cell development, differentiation, and function. Here, we examined the impact of the microbiota on CD8(+) T cell memory. Antigen-activated CD8(+) T cells transferred into germ-free mice failed to transition into long-lived memory cells and had transcriptional impairments in core genes associated with oxidative metabolism. The microbiota-derived short-chain fatty acid (SCFA) butyrate promoted cellular metabolism, enhanced memory potential of activated CD8(+) T cells, and SCFAs were required for optimal recall responses upon antigen re-encounter. Mechanistic experiments revealed that butyrate uncoupled the tricarboxylic acid cycle from glycolytic input in CD8(+) T cells, which allowed preferential fueling of oxidative phosphorylation through sustained glutamine utilization and fatty acid catabolism. Our findings reveal a role for the microbiota in promoting CD8(+) T cell long-term survival as memory cells and suggest that microbial metabolites guide the metabolic rewiring of activated CD8(+) T cells to enable this transition.