Microbiota-derived short-chain fatty acids promote the memory potential of antigen-activated CD8+ T cells

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;Bedoui, Sammy

Andreas Kupz

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.

Journal

Immunity

Publication Name

N/A

Volume

ISBN/ISSN

1097-4180

Edition

N/A

Issue

N/A

Pages Count

Location

N/A

Publisher

Cell Press

Publisher Url

N/A

Publisher Location

N/A

Publish Date

N/A

Url

N/A

Date

N/A

EISSN

N/A

DOI

10.1016/j.immuni.2019.06.002