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

被引：66

作者：

Luda, Katarzyna M. ^{[1
,2
]}

Longo, Joseph ^{[1
]}

Kitchen-Goosen, Susan M. ^{[1
]}

Duimstra, Lauren R. ^{[1
]}

Ma, Eric H. ^{[1
]}

Watson, McLane J. ^{[1
]}

Oswald, Brandon M. ^{[1
]}

Fu, Zhen ^{[3
]}

Madaj, Zachary ^{[3
]}

Kupai, Ariana ^{[4
]}

Dickson, Bradley M. ^{[4
]}

DeCamp, Lisa M. ^{[1
]}

Dahabieh, Michael S. ^{[1
]}

Compton, Shelby E. ^{[1
]}

Teis, Robert ^{[1
]}

Kaymak, Irem ^{[1
]}

Lau, Kin H. ^{[3
]}

Kelly, Daniel P. ^{[5
,6
]}

Puchalska, Patrycja ^{[7
]}

Williams, Kelsey S. ^{[1
]}

Krawczyk, Connie M. ^{[1
]}

Levesque, Dominique ^{[8
]}

Boisvert, Francois-Michel ^{[8
]}

Sheldon, Ryan D. ^{[9
]}

Rothbart, Scott B. ^{[4
]}

Crawford, Peter A. ^{[7
,10
]}

Jones, Russell G. ^{[1
]}

机构：

[1] Van Andel Inst, Dept Metab & Nutr Programming, Grand Rapids, MI 49503 USA

[2] Univ Copenhagen, Novo Nord Fdn Ctr Basic Metab Res, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark

[3] Van Andel Inst, Bioinformat & Biostat Core, Grand Rapids, MI 49503 USA

[4] Van Andel Inst, Dept Epigenet, Grand Rapids, MI 49503 USA

[5] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA

[6] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA

[7] Univ Minnesota, Dept Med, Div Mol Med, Minneapolis, MN 55455 USA

[8] Univ Sherbrooke, Dept Anat & Cell Biol, Sherbrooke, PQ J1E 4K8, Canada

[9] Van Andel Inst, Mass Spectrometry Core, Grand Rapids, MI 49503 USA

[10] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA

来源：

IMMUNITY | 2023年 / 56卷 / 09期

关键词：

T-CELLS; BETA-HYDROXYBUTYRATE; METABOLIC ADAPTATION; NLRP3; INFLAMMASOME; EPIGENETIC CONTROL; FUEL METABOLISM; GENE-EXPRESSION; KETONE-BODIES; RESPONSES; ROLES;

D O I：

10.1016/j.immuni.2023.07.002

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Environmental nutrient availability influences T cell metabolism, impacting T cell function and shaping immune outcomes. Here, we identified ketone bodies (KBs)-including j3-hydroxybutyrate (j3OHB) and acetoacetate (AcAc)-as essential fuels supporting CD8+ T cell metabolism and effector function. j3OHB 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, j3OHB 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.

引用

页码：2021 / +

页数：24

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