Ketolysis drives CD8+ T cell effector function through effects on histone acetylation

Katarzyna M. Luda; Joseph Longo; Susan M. Kitchen-Goosen; Lauren R. Duimstra; Eric H. Ma; McLane J. Watson; Brandon M. Oswald; Zhen Fu; Zachary Madaj; Ariana Kupai; Bradley M. Dickson; Lisa M. DeCamp; Michael S. Dahabieh; Shelby E. Compton; Robert Teis; Irem Kaymak; Kin H. Lau; Daniel P. Kelly; Patrycja Puchalska; Kelsey S. Williams; Connie M. Krawczyk; Dominique Lévesque; François Michel Boisvert; Ryan D. Sheldon; Scott B. Rothbart; Peter A. Crawford; Russell G. Jones

doi:10.1016/j.immuni.2023.07.002

Ketolysis drives CD8⁺ T cell effector function through effects on histone acetylation

Katarzyna M. Luda, Joseph Longo, Susan M. Kitchen-Goosen, Lauren R. Duimstra, Eric H. Ma, McLane J. Watson, Brandon M. Oswald, Zhen Fu, Zachary Madaj, Ariana Kupai, Bradley M. Dickson, Lisa M. DeCamp, Michael S. Dahabieh, Shelby E. Compton, Robert Teis, Irem Kaymak, Kin H. Lau, Daniel P. Kelly, Patrycja Puchalska, Kelsey S. WilliamsConnie M. Krawczyk, Dominique Lévesque, François Michel Boisvert, Ryan D. Sheldon, Scott B. Rothbart, Peter A. Crawford, Russell G. Jones

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

Environmental nutrient availability influences T cell metabolism, impacting T cell function and shaping immune outcomes. Here, we identified ketone bodies (KBs)—including β-hydroxybutyrate (βOHB) and acetoacetate (AcAc)—as essential fuels supporting CD8⁺ T cell metabolism and effector function. βOHB directly increased CD8⁺ T effector (Teff) cell cytokine production and cytolytic activity, and KB oxidation (ketolysis) was required for Teff cell responses to bacterial infection and tumor challenge. CD8⁺ Teff cells preferentially used KBs over glucose to fuel the tricarboxylic acid (TCA) cycle in vitro and in vivo. KBs directly boosted the respiratory capacity and TCA cycle-dependent metabolic pathways that fuel CD8⁺ T cell function. Mechanistically, βOHB was a major substrate for acetyl-CoA production in CD8⁺ T cells and regulated effector responses through effects on histone acetylation. Together, our results identify cell-intrinsic ketolysis as a metabolic and epigenetic driver of optimal CD8⁺ T cell effector responses.

Original language	English (US)
Pages (from-to)	2021-2035.e8
Journal	Immunity
Volume	56
Issue number	9
DOIs	https://doi.org/10.1016/j.immuni.2023.07.002
State	Published - Sep 12 2023

Bibliographical note

Publisher Copyright:
© 2023 The Authors

Keywords

CD8 T cells
TCA cycle
acetyl-CoA
cancer immunology
effector function
epigenetics
ketolysis
ketone bodies
metabolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Luda, K. M., Longo, J., Kitchen-Goosen, S. M., Duimstra, L. R., Ma, E. H., Watson, M. J., Oswald, B. M., Fu, Z., Madaj, Z., Kupai, A., Dickson, B. M., DeCamp, L. M., Dahabieh, M. S., Compton, S. E., Teis, R., Kaymak, I., Lau, K. H., Kelly, D. P., Puchalska, P., ... Jones, R. G. (2023). Ketolysis drives CD8⁺ T cell effector function through effects on histone acetylation. Immunity, 56(9), 2021-2035.e8. https://doi.org/10.1016/j.immuni.2023.07.002

Luda, KM, Longo, J, Kitchen-Goosen, SM, Duimstra, LR, Ma, EH, Watson, MJ, Oswald, BM, Fu, Z, Madaj, Z, Kupai, A, Dickson, BM, DeCamp, LM, Dahabieh, MS, Compton, SE, Teis, R, Kaymak, I, Lau, KH, Kelly, DP, Puchalska, P, Williams, KS, Krawczyk, CM, Lévesque, D, Boisvert, FM, Sheldon, RD, Rothbart, SB, Crawford, PA & Jones, RG 2023, 'Ketolysis drives CD8⁺ T cell effector function through effects on histone acetylation', Immunity, vol. 56, no. 9, pp. 2021-2035.e8. https://doi.org/10.1016/j.immuni.2023.07.002

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abstract = "Environmental nutrient availability influences T cell metabolism, impacting T cell function and shaping immune outcomes. Here, we identified ketone bodies (KBs)—including β-hydroxybutyrate (βOHB) and acetoacetate (AcAc)—as essential fuels supporting CD8+ T cell metabolism and effector function. βOHB directly increased CD8+ T effector (Teff) cell cytokine production and cytolytic activity, and KB oxidation (ketolysis) was required for Teff cell responses to bacterial infection and tumor challenge. CD8+ Teff cells preferentially used KBs over glucose to fuel the tricarboxylic acid (TCA) cycle in vitro and in vivo. KBs directly boosted the respiratory capacity and TCA cycle-dependent metabolic pathways that fuel CD8+ T cell function. Mechanistically, βOHB was a major substrate for acetyl-CoA production in CD8+ T cells and regulated effector responses through effects on histone acetylation. Together, our results identify cell-intrinsic ketolysis as a metabolic and epigenetic driver of optimal CD8+ T cell effector responses.",

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AU - Longo, Joseph

AU - Kitchen-Goosen, Susan M.

AU - Duimstra, Lauren R.

AU - Ma, Eric H.

AU - Watson, McLane J.

AU - Oswald, Brandon M.

AU - Fu, Zhen

AU - Madaj, Zachary

AU - Kupai, Ariana

AU - Dickson, Bradley M.

AU - DeCamp, Lisa M.

AU - Dahabieh, Michael S.

AU - Compton, Shelby E.

AU - Teis, Robert

AU - Kaymak, Irem

AU - Lau, Kin H.

AU - Kelly, Daniel P.

AU - Puchalska, Patrycja

AU - Williams, Kelsey S.

AU - Krawczyk, Connie M.

AU - Lévesque, Dominique

AU - Boisvert, François Michel

AU - Sheldon, Ryan D.

AU - Rothbart, Scott B.

AU - Crawford, Peter A.

AU - Jones, Russell G.

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