Microbiota-Derived Short-Chain Fatty Acids Promote the Memory Potential of Antigen-Activated CD8+ T Cells

Abstract

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.

Keywords: CD8(+) T cells; T cell metabolism; butyrate; fatty acid oxidation; memory differentiation; microbiota; short-chain fatty acids.