The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo

Julianna Blagih; François Coulombe; Emma E Vincent; Fanny Dupuy; Gabriela Galicia-Vázquez; Ekaterina Yurchenko; Thomas C Raissi; Gerritje J W van der Windt; Benoit Viollet; Erika L Pearce; Jerry Pelletier; Ciriaco A Piccirillo; Connie M Krawczyk; Maziar Divangahi; Russell G Jones

doi:10.1016/j.immuni.2014.12.030

The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo

Julianna Blagih, François Coulombe, Emma E Vincent, Fanny Dupuy, Gabriela Galicia-Vázquez, Ekaterina Yurchenko, Thomas C Raissi, Gerritje J W van der Windt, Benoit Viollet, Erika L Pearce, Jerry Pelletier, Ciriaco A Piccirillo, Connie M Krawczyk, Maziar Divangahi, Russell G Jones

Research output: Contribution to journal › Article (Academic Journal) › peer-review

430 Citations (Scopus)

Abstract

Naive T cells undergo metabolic reprogramming to support the increased energetic and biosynthetic demands of effector T cell function. However, how nutrient availability influences T cell metabolism and function remains poorly understood. Here we report plasticity in effector T cell metabolism in response to changing nutrient availability. Activated T cells were found to possess a glucose-sensitive metabolic checkpoint controlled by the energy sensor AMP-activated protein kinase (AMPK) that regulated mRNA translation and glutamine-dependent mitochondrial metabolism to maintain T cell bioenergetics and viability. T cells lacking AMPKα1 displayed reduced mitochondrial bioenergetics and cellular ATP in response to glucose limitation in vitro or pathogenic challenge in vivo. Finally, we demonstrated that AMPKα1 is essential for T helper 1 (Th1) and Th17 cell development and primary T cell responses to viral and bacterial infections in vivo. Our data highlight AMPK-dependent regulation of metabolic homeostasis as a key regulator of T cell-mediated adaptive immunity.

Original language	English
Pages (from-to)	41-54
Number of pages	14
Journal	Immunity
Volume	42
Issue number	1
DOIs	https://doi.org/10.1016/j.immuni.2014.12.030
Publication status	Published - 20 Jan 2015

Keywords

AMP-Activated Protein Kinases
Adaptation, Physiological
Animals
CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
Cells, Cultured
Cellular Reprogramming
Energy Metabolism
Glucose
Glutamine
Humans
Immunomodulation
Influenza A Virus, H1N1 Subtype
Lymphocyte Activation
Metabolomics
Mice
Mice, Inbred C57BL
Mice, Knockout
Orthomyxoviridae Infections
Protein Biosynthesis
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

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10.1016/j.immuni.2014.12.030

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Dr Emma E Vincent
- emma.vincentbristol.acuk
- Bristol Medical School (THS) - Senior Lecturer in Molecular Metabolism
- School of Cellular and Molecular Medicine - Research Fellow
- Bristol Population Health Science Institute
- Cancer
Person: Academic , Academic , Member

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Blagih, J., Coulombe, F., Vincent, E. E., Dupuy, F., Galicia-Vázquez, G., Yurchenko, E., Raissi, T. C., van der Windt, G. J. W., Viollet, B., Pearce, E. L., Pelletier, J., Piccirillo, C. A., Krawczyk, C. M., Divangahi, M., & Jones, R. G. (2015). The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. Immunity, 42(1), 41-54. https://doi.org/10.1016/j.immuni.2014.12.030

@article{bf8366c122b44763bf0a02c51f9fc4c6,

title = "The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo",

abstract = "Naive T cells undergo metabolic reprogramming to support the increased energetic and biosynthetic demands of effector T cell function. However, how nutrient availability influences T cell metabolism and function remains poorly understood. Here we report plasticity in effector T cell metabolism in response to changing nutrient availability. Activated T cells were found to possess a glucose-sensitive metabolic checkpoint controlled by the energy sensor AMP-activated protein kinase (AMPK) that regulated mRNA translation and glutamine-dependent mitochondrial metabolism to maintain T cell bioenergetics and viability. T cells lacking AMPKα1 displayed reduced mitochondrial bioenergetics and cellular ATP in response to glucose limitation in vitro or pathogenic challenge in vivo. Finally, we demonstrated that AMPKα1 is essential for T helper 1 (Th1) and Th17 cell development and primary T cell responses to viral and bacterial infections in vivo. Our data highlight AMPK-dependent regulation of metabolic homeostasis as a key regulator of T cell-mediated adaptive immunity.",

keywords = "AMP-Activated Protein Kinases, Adaptation, Physiological, Animals, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cells, Cultured, Cellular Reprogramming, Energy Metabolism, Glucose, Glutamine, Humans, Immunomodulation, Influenza A Virus, H1N1 Subtype, Lymphocyte Activation, Metabolomics, Mice, Mice, Inbred C57BL, Mice, Knockout, Orthomyxoviridae Infections, Protein Biosynthesis, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't",

author = "Julianna Blagih and Fran{\c c}ois Coulombe and Vincent, {Emma E} and Fanny Dupuy and Gabriela Galicia-V{\'a}zquez and Ekaterina Yurchenko and Raissi, {Thomas C} and {van der Windt}, {Gerritje J W} and Benoit Viollet and Pearce, {Erika L} and Jerry Pelletier and Piccirillo, {Ciriaco A} and Krawczyk, {Connie M} and Maziar Divangahi and Jones, {Russell G}",

year = "2015",

month = jan,

day = "20",

doi = "10.1016/j.immuni.2014.12.030",

language = "English",

volume = "42",

pages = "41--54",

journal = "Immunity",

issn = "1074-7613",

publisher = "Cell Press",

number = "1",

}

Blagih, J, Coulombe, F, Vincent, EE, Dupuy, F, Galicia-Vázquez, G, Yurchenko, E, Raissi, TC, van der Windt, GJW, Viollet, B, Pearce, EL, Pelletier, J, Piccirillo, CA, Krawczyk, CM, Divangahi, M & Jones, RG 2015, 'The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo', Immunity, vol. 42, no. 1, pp. 41-54. https://doi.org/10.1016/j.immuni.2014.12.030

TY - JOUR

T1 - The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo

AU - Blagih, Julianna

AU - Coulombe, François

AU - Vincent, Emma E

AU - Dupuy, Fanny

AU - Galicia-Vázquez, Gabriela

AU - Yurchenko, Ekaterina

AU - Raissi, Thomas C

AU - van der Windt, Gerritje J W

AU - Viollet, Benoit

AU - Pearce, Erika L

AU - Pelletier, Jerry

AU - Piccirillo, Ciriaco A

AU - Krawczyk, Connie M

AU - Divangahi, Maziar

AU - Jones, Russell G

PY - 2015/1/20

Y1 - 2015/1/20

N2 - Naive T cells undergo metabolic reprogramming to support the increased energetic and biosynthetic demands of effector T cell function. However, how nutrient availability influences T cell metabolism and function remains poorly understood. Here we report plasticity in effector T cell metabolism in response to changing nutrient availability. Activated T cells were found to possess a glucose-sensitive metabolic checkpoint controlled by the energy sensor AMP-activated protein kinase (AMPK) that regulated mRNA translation and glutamine-dependent mitochondrial metabolism to maintain T cell bioenergetics and viability. T cells lacking AMPKα1 displayed reduced mitochondrial bioenergetics and cellular ATP in response to glucose limitation in vitro or pathogenic challenge in vivo. Finally, we demonstrated that AMPKα1 is essential for T helper 1 (Th1) and Th17 cell development and primary T cell responses to viral and bacterial infections in vivo. Our data highlight AMPK-dependent regulation of metabolic homeostasis as a key regulator of T cell-mediated adaptive immunity.

AB - Naive T cells undergo metabolic reprogramming to support the increased energetic and biosynthetic demands of effector T cell function. However, how nutrient availability influences T cell metabolism and function remains poorly understood. Here we report plasticity in effector T cell metabolism in response to changing nutrient availability. Activated T cells were found to possess a glucose-sensitive metabolic checkpoint controlled by the energy sensor AMP-activated protein kinase (AMPK) that regulated mRNA translation and glutamine-dependent mitochondrial metabolism to maintain T cell bioenergetics and viability. T cells lacking AMPKα1 displayed reduced mitochondrial bioenergetics and cellular ATP in response to glucose limitation in vitro or pathogenic challenge in vivo. Finally, we demonstrated that AMPKα1 is essential for T helper 1 (Th1) and Th17 cell development and primary T cell responses to viral and bacterial infections in vivo. Our data highlight AMPK-dependent regulation of metabolic homeostasis as a key regulator of T cell-mediated adaptive immunity.

KW - AMP-Activated Protein Kinases

KW - Adaptation, Physiological

KW - Animals

KW - CD4-Positive T-Lymphocytes

KW - CD8-Positive T-Lymphocytes

KW - Cells, Cultured

KW - Cellular Reprogramming

KW - Energy Metabolism

KW - Glucose

KW - Glutamine

KW - Humans

KW - Immunomodulation

KW - Influenza A Virus, H1N1 Subtype

KW - Lymphocyte Activation

KW - Metabolomics

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Orthomyxoviridae Infections

KW - Protein Biosynthesis

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1016/j.immuni.2014.12.030

DO - 10.1016/j.immuni.2014.12.030

M3 - Article (Academic Journal)

C2 - 25607458

SN - 1074-7613

VL - 42

SP - 41

EP - 54

JO - Immunity

JF - Immunity

IS - 1

ER -

The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo

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Keywords

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Dr Emma E Vincent

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