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^*

^*Corresponding author af dette arbejde

Sakamoto Group

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

29 Citationer (Scopus)

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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.

Originalsprog	Engelsk
Tidsskrift	Immunity
Vol/bind	56
Udgave nummer	9
Sider (fra-til)	2021-2035.e8
Antal sider	24
ISSN	1074-7613
DOI	https://doi.org/10.1016/j.immuni.2023.07.002
Status	Udgivet - 2023

Bibliografisk note

Funding Information:
We acknowledge Drs. Ralph DeBerardinis, Julian Lum, Sara Nowinski, Evan Lien, and members of the Jones and Krawczyk laboratories for scientific discussions contributing to this manuscript. We thank Teresa Leone, Matthew Vos, Jeanie Wedberg, Margene Brewer, and Michelle Minard for administrative assistance. We thank members of the Van Andel Institute (VAI) Core Facilities (metabolomics and bioenergetics, genomics, bioinformatics and biostatistics, flow cytometry, vivarium) for technical assistance. J.L. is supported by a VAI Metabolism & Nutrition (MeNu) Program Pathway-to-Independence Award and Canadian Institutes of Health Research (CIHR) Fellowship (MFE-181903). M.J.W. is supported by a National Cancer Institute (NCI) T32 training grant (T32CA251066-01A1). D.P.K. is supported by the National Institutes of Health (NIH, R01HL128349 and R01HL151345). C.M.K. is supported by the National Institute of Allergy and Infectious Diseases (NIAID, R21AI153997) and VAI. F.-M.B. is a FRQS Senior Scholar (281824) and is supported by the National Sciences and Engineering Research Council of Canada (RGPIN-2018-05414). S.B.R. is supported by the National Institute of General Medical Sciences (NIGMS, R35GM124736) and VAI. P.A.C. and P.P. are supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, DK091538) and National Institute on Aging (NIA, AG069781). R.G.J. is supported by the Paul G. Allen Frontiers Group Distinguished Investigator Program, NIAID (R01AI165722), and VAI. Conceptualization, K.M.L. and R.G.J.; experimental design, K.M.L. J.L. E.H.M. D.P.K. P.P. C.M.K. F.-M.B. R.D.S. S.B.R. P.A.C. and R.G.J.; investigation, K.M.L. J.L. S.M.K.-G. L.R.D. E.H.M. M.J.W. B.M.O. A.K. L.M.D. M.S.D. S.E.C. R.T. and I.K.; data analysis, K.M.L. J.L. S.K.M.-G. E.H.M. M.J.W. B.M.O. Z.F. Z.M. B.M.D. K.H.L. K.S.W. D.L. R.D.S. and R.G.J.; writing – original draft, K.M.L. K.S.W. and R.G.J.; writing – editing, K.M.L. J.L. C.M.K. S.B.R. P.A.C. and R.G.J.; visualization, Z.F. and K.S.W.; supervision, R.G.J.; funding acquisition, R.G.J. R.G.J. is a scientific advisor for Agios Pharmaceuticals and Servier Pharmaceuticals and is a member of the Scientific Advisory Board of Immunomet Therapeutics. We support inclusive, diverse, and equitable conduct of research.

Funding Information:
We acknowledge Drs. Ralph DeBerardinis, Julian Lum, Sara Nowinski, Evan Lien, and members of the Jones and Krawczyk laboratories for scientific discussions contributing to this manuscript. We thank Teresa Leone, Matthew Vos, Jeanie Wedberg, Margene Brewer, and Michelle Minard for administrative assistance. We thank members of the Van Andel Institute (VAI) Core Facilities (metabolomics and bioenergetics, genomics, bioinformatics and biostatistics, flow cytometry, vivarium) for technical assistance. J.L. is supported by a VAI Metabolism & Nutrition (MeNu) Program Pathway-to-Independence Award and Canadian Institutes of Health Research (CIHR) Fellowship ( MFE-181903 ). M.J.W. is supported by a National Cancer Institute (NCI) T32 training grant ( T32CA251066-01A1 ). D.P.K. is supported by the National Institutes of Health (NIH, R01HL128349 and R01HL151345 ). C.M.K. is supported by the National Institute of Allergy and Infectious Diseases (NIAID, R21AI153997 ) and VAI . F.-M.B. is a FRQS Senior Scholar ( 281824 ) and is supported by the National Sciences and Engineering Research Council of Canada ( RGPIN-2018-05414 ). S.B.R. is supported by the National Institute of General Medical Sciences (NIGMS, R35GM124736 ) and VAI . P.A.C. and P.P. are supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, DK091538 ) and National Institute on Aging (NIA, AG069781 ). R.G.J. is supported by the Paul G. Allen Frontiers Group Distinguished Investigator Program , NIAID ( R01AI165722 ), and VAI .

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Citationsformater

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

Ketolysis drives CD8⁺ T cell effector function through effects on histone acetylation. / Luda, Katarzyna M.; Longo, Joseph; Kitchen-Goosen, Susan M.; Duimstra, Lauren R.; Ma, Eric H.; Watson, McLane J.; Oswald, Brandon M.; Fu, Zhen; Madaj, Zachary; Kupai, Ariana; Dickson, Bradley M.; DeCamp, Lisa M.; Dahabieh, Michael S.; Compton, Shelby E.; Teis, Robert; Kaymak, Irem; Lau, Kin H.; Kelly, Daniel P.; Puchalska, Patrycja; Williams, Kelsey S.; Krawczyk, Connie M.; Lévesque, Dominique; Boisvert, François Michel; Sheldon, Ryan D.; Rothbart, Scott B.; Crawford, Peter A.; Jones, Russell G.

I: Immunity, Bind 56, Nr. 9, 2023, s. 2021-2035.e8.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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, bind 56, nr. 9, s. 2021-2035.e8. https://doi.org/10.1016/j.immuni.2023.07.002

Luda, Katarzyna M. ; Longo, Joseph ; Kitchen-Goosen, Susan M. ; Duimstra, Lauren R. ; Ma, Eric H. ; Watson, McLane J. ; Oswald, Brandon M. ; Fu, Zhen ; Madaj, Zachary ; Kupai, Ariana ; Dickson, Bradley M. ; DeCamp, Lisa M. ; Dahabieh, Michael S. ; Compton, Shelby E. ; Teis, Robert ; Kaymak, Irem ; Lau, Kin H. ; Kelly, Daniel P. ; Puchalska, Patrycja ; Williams, Kelsey S. ; Krawczyk, Connie M. ; Lévesque, Dominique ; Boisvert, François Michel ; Sheldon, Ryan D. ; Rothbart, Scott B. ; Crawford, Peter A. ; Jones, Russell G. / Ketolysis drives CD8⁺ T cell effector function through effects on histone acetylation. I: Immunity. 2023 ; Bind 56, Nr. 9. s. 2021-2035.e8.

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title = "Ketolysis drives CD8+ T cell effector function through effects on histone acetylation",

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.",

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

author = "Luda, {Katarzyna M.} and Joseph Longo and Kitchen-Goosen, {Susan M.} and Duimstra, {Lauren R.} and Ma, {Eric H.} and Watson, {McLane J.} and Oswald, {Brandon M.} and Zhen Fu and Zachary Madaj and Ariana Kupai and Dickson, {Bradley M.} and DeCamp, {Lisa M.} and Dahabieh, {Michael S.} and Compton, {Shelby E.} and Robert Teis and Irem Kaymak and Lau, {Kin H.} and Kelly, {Daniel P.} and Patrycja Puchalska and Williams, {Kelsey S.} and Krawczyk, {Connie M.} and Dominique L{\'e}vesque and Boisvert, {Fran{\c c}ois Michel} and Sheldon, {Ryan D.} and Rothbart, {Scott B.} and Crawford, {Peter A.} and Jones, {Russell G.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

doi = "10.1016/j.immuni.2023.07.002",

language = "English",

volume = "56",

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T1 - Ketolysis drives CD8+ T cell effector function through effects on histone acetylation

AU - Luda, Katarzyna M.

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.

PY - 2023

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N2 - 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.

AB - 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.

KW - acetyl-CoA

KW - cancer immunology

KW - CD8 T cells

KW - effector function

KW - epigenetics

KW - ketolysis

KW - ketone bodies

KW - metabolism

KW - TCA cycle

U2 - 10.1016/j.immuni.2023.07.002

DO - 10.1016/j.immuni.2023.07.002

M3 - Journal article

C2 - 37516105

AN - SCOPUS:85169013765

VL - 56

SP - 2021-2035.e8

JO - Immunity

JF - Immunity

SN - 1074-7613

IS - 9

ER -