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

Annabell Bachem, Christina Makhlouf, Katrina J. Binger, David P. de Souza, Deidra Tull, Katharina Hochheiser, Paul G. Whitney, Daniel Fernandez-Ruiz, Sabrina Dähling, Wolfgang Kastenmüller, Johanna Jönsson, Elise Gressier, Andrew M. Lew, Carolina Perdomo, Andreas Kupz, William Figgett, Fabienne Mackay, Moshe Oleshansky, Brendan E. Russ, Ian A. Parish & 5 others Axel Kallies, Malcolm J. McConville, Stephen J. Turner, Thomas Gebhardt, Sammy Bedoui

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)285-297
Number of pages13
JournalImmunity
Volume51
Issue number2
DOIs
Publication statusPublished - 20 Aug 2019

Keywords

  • butyrate
  • CD8 T cells
  • fatty acid oxidation
  • memory differentiation
  • microbiota
  • short-chain fatty acids
  • T cell metabolism

Cite this

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. / Microbiota-Derived Short-Chain Fatty Acids Promote the Memory Potential of Antigen-Activated CD8+ T Cells. In: Immunity. 2019 ; Vol. 51, No. 2. 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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author = "Annabell Bachem and Christina Makhlouf and Binger, {Katrina J.} and {de Souza}, {David P.} and Deidra Tull and Katharina Hochheiser and Whitney, {Paul G.} and Daniel Fernandez-Ruiz and Sabrina D{\"a}hling and Wolfgang Kastenm{\"u}ller and Johanna J{\"o}nsson and Elise Gressier and Lew, {Andrew M.} and Carolina Perdomo and Andreas Kupz and William Figgett and Fabienne Mackay and Moshe Oleshansky and Russ, {Brendan E.} and Parish, {Ian A.} and Axel Kallies and McConville, {Malcolm J.} and Turner, {Stephen J.} and Thomas Gebhardt and Sammy Bedoui",
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Bachem, A, Makhlouf, C, Binger, KJ, de Souza, DP, Tull, D, Hochheiser, K, Whitney, PG, Fernandez-Ruiz, D, Dähling, S, Kastenmüller, W, Jönsson, J, Gressier, E, Lew, AM, Perdomo, C, Kupz, A, Figgett, W, Mackay, F, Oleshansky, M, Russ, BE, Parish, IA, Kallies, A, McConville, MJ, Turner, SJ, Gebhardt, T & Bedoui, S 2019, 'Microbiota-Derived Short-Chain Fatty Acids Promote the Memory Potential of Antigen-Activated CD8+ T Cells', Immunity, vol. 51, no. 2, pp. 285-297. https://doi.org/10.1016/j.immuni.2019.06.002

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.

In: Immunity, Vol. 51, No. 2, 20.08.2019, p. 285-297.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Bachem, Annabell

AU - Makhlouf, Christina

AU - Binger, Katrina J.

AU - de Souza, David P.

AU - Tull, Deidra

AU - Hochheiser, Katharina

AU - Whitney, Paul G.

AU - Fernandez-Ruiz, Daniel

AU - Dähling, Sabrina

AU - Kastenmüller, Wolfgang

AU - Jönsson, Johanna

AU - Gressier, Elise

AU - Lew, Andrew M.

AU - Perdomo, Carolina

AU - Kupz, Andreas

AU - Figgett, William

AU - Mackay, Fabienne

AU - Oleshansky, Moshe

AU - Russ, Brendan E.

AU - Parish, Ian A.

AU - Kallies, Axel

AU - McConville, Malcolm J.

AU - Turner, Stephen J.

AU - Gebhardt, Thomas

AU - Bedoui, Sammy

PY - 2019/8/20

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N2 - 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.

AB - 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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KW - CD8 T cells

KW - fatty acid oxidation

KW - memory differentiation

KW - microbiota

KW - short-chain fatty acids

KW - T cell metabolism

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