Distinct modes of mitochondrial metabolism uncouple T cell differentiation and function

Will Bailis, Justin A. Shyer, Jun Zhao, Juan Carlos Garcia Canaveras, Fatimah J. Al Khazal, Rihao Qu, Holly R. Steach, Piotr Bielecki, Omair Khan, Ruaidhri Jackson, Yuval Kluger, L James Maher III, Joshua Rabinowitz, Joe Craft, Richard A. Flavell

Research output: Contribution to journalLetter

3 Citations (Scopus)

Abstract

Activated CD4 T cells proliferate rapidly and remodel epigenetically before exiting the cell cycle and engaging acquired effector functions. Metabolic reprogramming from the naive state is required throughout these phases of activation1. In CD4 T cells, T-cell-receptor ligation—along with co-stimulatory and cytokine signals—induces a glycolytic anabolic program that is required for biomass generation, rapid proliferation and effector function2. CD4 T cell differentiation (proliferation and epigenetic remodelling) and function are orchestrated coordinately by signal transduction and transcriptional remodelling. However, it remains unclear whether these processes are regulated independently of one another by cellular biochemical composition. Here we demonstrate that distinct modes of mitochondrial metabolism support differentiation and effector functions of mouse T helper 1 (TH1) cells by biochemically uncoupling these two processes. We find that the tricarboxylic acid cycle is required for the terminal effector function of TH1 cells through succinate dehydrogenase (complex II), but that the activity of succinate dehydrogenase suppresses TH1 cell proliferation and histone acetylation. By contrast, we show that complex I of the electron transport chain, the malate–aspartate shuttle and mitochondrial citrate export are required to maintain synthesis of aspartate, which is necessary for the proliferation of T helper cells. Furthermore, we find that mitochondrial citrate export and the malate–aspartate shuttle promote histone acetylation, and specifically regulate the expression of genes involved in T cell activation. Combining genetic, pharmacological and metabolomics approaches, we demonstrate that the differentiation and terminal effector functions of T helper cells are biochemically uncoupled. These findings support a model in which the malate–aspartate shuttle, mitochondrial citrate export and complex I supply the substrates needed for proliferation and epigenetic remodelling early during T cell activation, whereas complex II consumes the substrates of these pathways, which antagonizes differentiation and enforces terminal effector function. Our data suggest that transcriptional programming acts together with a parallel biochemical network to enforce cell state.

Original languageEnglish (US)
JournalNature
DOIs
StatePublished - Jan 1 2019

Fingerprint

Cell Differentiation
Th1 Cells
T-Lymphocytes
Citric Acid
Succinate Dehydrogenase
Acetylation
Helper-Inducer T-Lymphocytes
Epigenomics
Histones
Cell Proliferation
Electron Transport Complex I
Metabolomics
Citric Acid Cycle
T-Cell Antigen Receptor
Biomass
Signal Transduction
Cell Cycle
Pharmacology
Cytokines
Gene Expression

ASJC Scopus subject areas

  • General

Cite this

Bailis, W., Shyer, J. A., Zhao, J., Canaveras, J. C. G., Al Khazal, F. J., Qu, R., ... Flavell, R. A. (2019). Distinct modes of mitochondrial metabolism uncouple T cell differentiation and function. Nature. https://doi.org/10.1038/s41586-019-1311-3

Distinct modes of mitochondrial metabolism uncouple T cell differentiation and function. / Bailis, Will; Shyer, Justin A.; Zhao, Jun; Canaveras, Juan Carlos Garcia; Al Khazal, Fatimah J.; Qu, Rihao; Steach, Holly R.; Bielecki, Piotr; Khan, Omair; Jackson, Ruaidhri; Kluger, Yuval; Maher III, L James; Rabinowitz, Joshua; Craft, Joe; Flavell, Richard A.

In: Nature, 01.01.2019.

Research output: Contribution to journalLetter

Bailis, W, Shyer, JA, Zhao, J, Canaveras, JCG, Al Khazal, FJ, Qu, R, Steach, HR, Bielecki, P, Khan, O, Jackson, R, Kluger, Y, Maher III, LJ, Rabinowitz, J, Craft, J & Flavell, RA 2019, 'Distinct modes of mitochondrial metabolism uncouple T cell differentiation and function', Nature. https://doi.org/10.1038/s41586-019-1311-3
Bailis, Will ; Shyer, Justin A. ; Zhao, Jun ; Canaveras, Juan Carlos Garcia ; Al Khazal, Fatimah J. ; Qu, Rihao ; Steach, Holly R. ; Bielecki, Piotr ; Khan, Omair ; Jackson, Ruaidhri ; Kluger, Yuval ; Maher III, L James ; Rabinowitz, Joshua ; Craft, Joe ; Flavell, Richard A. / Distinct modes of mitochondrial metabolism uncouple T cell differentiation and function. In: Nature. 2019.
@article{5319353263da4abcae34c73af8f72ca4,
title = "Distinct modes of mitochondrial metabolism uncouple T cell differentiation and function",
abstract = "Activated CD4 T cells proliferate rapidly and remodel epigenetically before exiting the cell cycle and engaging acquired effector functions. Metabolic reprogramming from the naive state is required throughout these phases of activation1. In CD4 T cells, T-cell-receptor ligation—along with co-stimulatory and cytokine signals—induces a glycolytic anabolic program that is required for biomass generation, rapid proliferation and effector function2. CD4 T cell differentiation (proliferation and epigenetic remodelling) and function are orchestrated coordinately by signal transduction and transcriptional remodelling. However, it remains unclear whether these processes are regulated independently of one another by cellular biochemical composition. Here we demonstrate that distinct modes of mitochondrial metabolism support differentiation and effector functions of mouse T helper 1 (TH1) cells by biochemically uncoupling these two processes. We find that the tricarboxylic acid cycle is required for the terminal effector function of TH1 cells through succinate dehydrogenase (complex II), but that the activity of succinate dehydrogenase suppresses TH1 cell proliferation and histone acetylation. By contrast, we show that complex I of the electron transport chain, the malate–aspartate shuttle and mitochondrial citrate export are required to maintain synthesis of aspartate, which is necessary for the proliferation of T helper cells. Furthermore, we find that mitochondrial citrate export and the malate–aspartate shuttle promote histone acetylation, and specifically regulate the expression of genes involved in T cell activation. Combining genetic, pharmacological and metabolomics approaches, we demonstrate that the differentiation and terminal effector functions of T helper cells are biochemically uncoupled. These findings support a model in which the malate–aspartate shuttle, mitochondrial citrate export and complex I supply the substrates needed for proliferation and epigenetic remodelling early during T cell activation, whereas complex II consumes the substrates of these pathways, which antagonizes differentiation and enforces terminal effector function. Our data suggest that transcriptional programming acts together with a parallel biochemical network to enforce cell state.",
author = "Will Bailis and Shyer, {Justin A.} and Jun Zhao and Canaveras, {Juan Carlos Garcia} and {Al Khazal}, {Fatimah J.} and Rihao Qu and Steach, {Holly R.} and Piotr Bielecki and Omair Khan and Ruaidhri Jackson and Yuval Kluger and {Maher III}, {L James} and Joshua Rabinowitz and Joe Craft and Flavell, {Richard A.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1038/s41586-019-1311-3",
language = "English (US)",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Distinct modes of mitochondrial metabolism uncouple T cell differentiation and function

AU - Bailis, Will

AU - Shyer, Justin A.

AU - Zhao, Jun

AU - Canaveras, Juan Carlos Garcia

AU - Al Khazal, Fatimah J.

AU - Qu, Rihao

AU - Steach, Holly R.

AU - Bielecki, Piotr

AU - Khan, Omair

AU - Jackson, Ruaidhri

AU - Kluger, Yuval

AU - Maher III, L James

AU - Rabinowitz, Joshua

AU - Craft, Joe

AU - Flavell, Richard A.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Activated CD4 T cells proliferate rapidly and remodel epigenetically before exiting the cell cycle and engaging acquired effector functions. Metabolic reprogramming from the naive state is required throughout these phases of activation1. In CD4 T cells, T-cell-receptor ligation—along with co-stimulatory and cytokine signals—induces a glycolytic anabolic program that is required for biomass generation, rapid proliferation and effector function2. CD4 T cell differentiation (proliferation and epigenetic remodelling) and function are orchestrated coordinately by signal transduction and transcriptional remodelling. However, it remains unclear whether these processes are regulated independently of one another by cellular biochemical composition. Here we demonstrate that distinct modes of mitochondrial metabolism support differentiation and effector functions of mouse T helper 1 (TH1) cells by biochemically uncoupling these two processes. We find that the tricarboxylic acid cycle is required for the terminal effector function of TH1 cells through succinate dehydrogenase (complex II), but that the activity of succinate dehydrogenase suppresses TH1 cell proliferation and histone acetylation. By contrast, we show that complex I of the electron transport chain, the malate–aspartate shuttle and mitochondrial citrate export are required to maintain synthesis of aspartate, which is necessary for the proliferation of T helper cells. Furthermore, we find that mitochondrial citrate export and the malate–aspartate shuttle promote histone acetylation, and specifically regulate the expression of genes involved in T cell activation. Combining genetic, pharmacological and metabolomics approaches, we demonstrate that the differentiation and terminal effector functions of T helper cells are biochemically uncoupled. These findings support a model in which the malate–aspartate shuttle, mitochondrial citrate export and complex I supply the substrates needed for proliferation and epigenetic remodelling early during T cell activation, whereas complex II consumes the substrates of these pathways, which antagonizes differentiation and enforces terminal effector function. Our data suggest that transcriptional programming acts together with a parallel biochemical network to enforce cell state.

AB - Activated CD4 T cells proliferate rapidly and remodel epigenetically before exiting the cell cycle and engaging acquired effector functions. Metabolic reprogramming from the naive state is required throughout these phases of activation1. In CD4 T cells, T-cell-receptor ligation—along with co-stimulatory and cytokine signals—induces a glycolytic anabolic program that is required for biomass generation, rapid proliferation and effector function2. CD4 T cell differentiation (proliferation and epigenetic remodelling) and function are orchestrated coordinately by signal transduction and transcriptional remodelling. However, it remains unclear whether these processes are regulated independently of one another by cellular biochemical composition. Here we demonstrate that distinct modes of mitochondrial metabolism support differentiation and effector functions of mouse T helper 1 (TH1) cells by biochemically uncoupling these two processes. We find that the tricarboxylic acid cycle is required for the terminal effector function of TH1 cells through succinate dehydrogenase (complex II), but that the activity of succinate dehydrogenase suppresses TH1 cell proliferation and histone acetylation. By contrast, we show that complex I of the electron transport chain, the malate–aspartate shuttle and mitochondrial citrate export are required to maintain synthesis of aspartate, which is necessary for the proliferation of T helper cells. Furthermore, we find that mitochondrial citrate export and the malate–aspartate shuttle promote histone acetylation, and specifically regulate the expression of genes involved in T cell activation. Combining genetic, pharmacological and metabolomics approaches, we demonstrate that the differentiation and terminal effector functions of T helper cells are biochemically uncoupled. These findings support a model in which the malate–aspartate shuttle, mitochondrial citrate export and complex I supply the substrates needed for proliferation and epigenetic remodelling early during T cell activation, whereas complex II consumes the substrates of these pathways, which antagonizes differentiation and enforces terminal effector function. Our data suggest that transcriptional programming acts together with a parallel biochemical network to enforce cell state.

UR - http://www.scopus.com/inward/record.url?scp=85067845391&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85067845391&partnerID=8YFLogxK

U2 - 10.1038/s41586-019-1311-3

DO - 10.1038/s41586-019-1311-3

M3 - Letter

C2 - 31217581

AN - SCOPUS:85067845391

JO - Nature

JF - Nature

SN - 0028-0836

ER -