Rapid effector function of memory CD8+ T cells requires an immediate-early glycolytic switch

Patrick M Gubser; Glenn R Bantug; Leyla Razik; Marco Fischer; Sarah Dimeloe; Gideon Hoenger; Bojana Durovic; Annaïse Jauch; Christoph Hess

doi:10.1038/ni.2687

Rapid effector function of memory CD8+ T cells requires an immediate-early glycolytic switch

Patrick M Gubser, Glenn R Bantug, Leyla Razik, Marco Fischer, Sarah Dimeloe, Gideon Hoenger, Bojana Durovic, Annaïse Jauch, Christoph Hess

Immunology and Immunotherapy

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

256 Citations (Scopus)

Abstract

Antigen-experienced memory T cells acquire effector function with innate-like kinetics; however, the metabolic requirements of these cells are unknown. Here we show that rapid interferon-γ (IFN-γ) production of effector memory (EM) CD8(+) T cells, activated through stimulation mediated by the T cell antigen receptor (TCR) and the costimulatory receptor CD28 or through cognate interactions, was linked to increased glycolytic flux. EM CD8(+) T cells exhibited more glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity at early time points, before proliferation commenced, than did naive cells activated under similar conditions. CD28 signaling via the serine-threonine kinase Akt and the metabolic-checkpoint kinase mTORC2 was needed to sustain TCR-mediated immediate-early glycolysis. Unlike glycolysis in proliferating cells, immediate-early glycolysis in memory CD8(+) T cells was rapamycin insensitive. Thus, CD8(+) memory T cells have an Akt-dependent 'imprinted' glycolytic potential that is required for efficient immediate-early IFN-γ recall responses.

Original language	English
Pages (from-to)	1064-72
Number of pages	9
Journal	Nature Immunology
Volume	14
Issue number	10
DOIs	https://doi.org/10.1038/ni.2687
Publication status	Published - Oct 2013

Keywords

CD8-Positive T-Lymphocytes
Chromatin Assembly and Disassembly
Epitopes, T-Lymphocyte
Glycolysis
Herpesvirus 4, Human
Humans
Immunologic Memory
Interferon-gamma
Lymphocyte Activation
Mechanistic Target of Rapamycin Complex 2
Metabolome
Metabolomics
Multiprotein Complexes
Promoter Regions, Genetic
Proto-Oncogene Proteins c-akt
Signal Transduction
TOR Serine-Threonine Kinases
Journal Article
Research Support, Non-U.S. Gov't

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10.1038/ni.2687

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title = "Rapid effector function of memory CD8+ T cells requires an immediate-early glycolytic switch",

abstract = "Antigen-experienced memory T cells acquire effector function with innate-like kinetics; however, the metabolic requirements of these cells are unknown. Here we show that rapid interferon-γ (IFN-γ) production of effector memory (EM) CD8(+) T cells, activated through stimulation mediated by the T cell antigen receptor (TCR) and the costimulatory receptor CD28 or through cognate interactions, was linked to increased glycolytic flux. EM CD8(+) T cells exhibited more glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity at early time points, before proliferation commenced, than did naive cells activated under similar conditions. CD28 signaling via the serine-threonine kinase Akt and the metabolic-checkpoint kinase mTORC2 was needed to sustain TCR-mediated immediate-early glycolysis. Unlike glycolysis in proliferating cells, immediate-early glycolysis in memory CD8(+) T cells was rapamycin insensitive. Thus, CD8(+) memory T cells have an Akt-dependent 'imprinted' glycolytic potential that is required for efficient immediate-early IFN-γ recall responses.",

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author = "Gubser, {Patrick M} and Bantug, {Glenn R} and Leyla Razik and Marco Fischer and Sarah Dimeloe and Gideon Hoenger and Bojana Durovic and Anna{\"i}se Jauch and Christoph Hess",

year = "2013",

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doi = "10.1038/ni.2687",

language = "English",

volume = "14",

pages = "1064--72",

journal = "Nature Immunology",

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AU - Gubser, Patrick M

AU - Bantug, Glenn R

AU - Razik, Leyla

AU - Fischer, Marco

AU - Dimeloe, Sarah

AU - Hoenger, Gideon

AU - Durovic, Bojana

AU - Jauch, Annaïse

AU - Hess, Christoph

PY - 2013/10

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N2 - Antigen-experienced memory T cells acquire effector function with innate-like kinetics; however, the metabolic requirements of these cells are unknown. Here we show that rapid interferon-γ (IFN-γ) production of effector memory (EM) CD8(+) T cells, activated through stimulation mediated by the T cell antigen receptor (TCR) and the costimulatory receptor CD28 or through cognate interactions, was linked to increased glycolytic flux. EM CD8(+) T cells exhibited more glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity at early time points, before proliferation commenced, than did naive cells activated under similar conditions. CD28 signaling via the serine-threonine kinase Akt and the metabolic-checkpoint kinase mTORC2 was needed to sustain TCR-mediated immediate-early glycolysis. Unlike glycolysis in proliferating cells, immediate-early glycolysis in memory CD8(+) T cells was rapamycin insensitive. Thus, CD8(+) memory T cells have an Akt-dependent 'imprinted' glycolytic potential that is required for efficient immediate-early IFN-γ recall responses.

AB - Antigen-experienced memory T cells acquire effector function with innate-like kinetics; however, the metabolic requirements of these cells are unknown. Here we show that rapid interferon-γ (IFN-γ) production of effector memory (EM) CD8(+) T cells, activated through stimulation mediated by the T cell antigen receptor (TCR) and the costimulatory receptor CD28 or through cognate interactions, was linked to increased glycolytic flux. EM CD8(+) T cells exhibited more glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity at early time points, before proliferation commenced, than did naive cells activated under similar conditions. CD28 signaling via the serine-threonine kinase Akt and the metabolic-checkpoint kinase mTORC2 was needed to sustain TCR-mediated immediate-early glycolysis. Unlike glycolysis in proliferating cells, immediate-early glycolysis in memory CD8(+) T cells was rapamycin insensitive. Thus, CD8(+) memory T cells have an Akt-dependent 'imprinted' glycolytic potential that is required for efficient immediate-early IFN-γ recall responses.

KW - CD8-Positive T-Lymphocytes

KW - Chromatin Assembly and Disassembly

KW - Epitopes, T-Lymphocyte

KW - Glycolysis

KW - Herpesvirus 4, Human

KW - Humans

KW - Immunologic Memory

KW - Interferon-gamma

KW - Lymphocyte Activation

KW - Mechanistic Target of Rapamycin Complex 2

KW - Metabolome

KW - Metabolomics

KW - Multiprotein Complexes

KW - Promoter Regions, Genetic

KW - Proto-Oncogene Proteins c-akt

KW - Signal Transduction

KW - TOR Serine-Threonine Kinases

KW - Journal Article

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

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DO - 10.1038/ni.2687

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EP - 1072

JO - Nature Immunology

JF - Nature Immunology

IS - 10

ER -

Rapid effector function of memory CD8+ T cells requires an immediate-early glycolytic switch

Abstract

Keywords

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