Bachem, Annabell, Makhlouf, Christina, Binger, Katrina J., de Souza, David P., Tull, Deidra, Hochheiser, Katharina, Whitney, Paul G., Fernandez-Ruiz, Daniel, Dähling, Sabrina, Kastenmüller, Wolfgang, Jönsson, Johanna, Gressier, Elise, Lew, Andrew M., Perdomo, Carolina, Kupz, Andreas, Figgett, William, Mackay, Fabienne, Oleshansky, Moshe, Russ, Brendan E., Parish, Ian A., Kallies, Axel, McConville, Malcolm J., Turner, Stephen J., Gebhardt, Thomas, and Bedoui, Sammy (2019) Microbiota-derived short-chain fatty acids promote the memory potential of antigen-activated CD8+ T cells. Immunity, 51. pp. 285-297.

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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.

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