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Immunity. 2019 Aug 20;51(2):285-297.e5. doi: 10.1016/j.immuni.2019.06.002. Epub 2019 Jul 1.

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

Author information

1
Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC 3010, Australia.
2
Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC 3010, Australia.
3
Institute of Systems Immunology, University of Würzburg, 97070 Würzburg, Germany.
4
Immunology Division, Walter and Eliza Hall Institute for Medical Research, Parkville, VIC 3010, Australia.
5
Department of Immunology, Max-Planck Institute for Infection Biology, Berlin, Germany.
6
Department of Immunology, Max-Planck Institute for Infection Biology, Berlin, Germany; Centre for Biosecurity and Tropical Infectious Diseases, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD, Australia.
7
Department of Microbiology, Monash University, Clayton, VIC 3800, Australia.
8
Cancer Immunology Program, Peter MacCallum Cancer Centre, Parkville, VIC 3010, Australia.
9
Department of Microbiology and Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: sbedoui@unimelb.edu.au.

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

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