13C tracer analysis reveals the landscape of metabolic checkpoints in human CD8+ T cell differentiation and exhaustion
Naïve T cells remain in an actively maintained state of quiescence until activation by antigenic signals, upon which they start to proliferate and generate effector cells to initiate a functional immune response. Metabolic reprogramming is essential to meet the biosynthetic demands of the differenti...
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| Vydáno v: | Frontiers in immunology Ročník 14; s. 1267816 |
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| Jazyk: | angličtina |
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Frontiers Media S.A
19.10.2023
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| ISSN: | 1664-3224, 1664-3224 |
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| Abstract | Naïve T cells remain in an actively maintained state of quiescence until activation by antigenic signals, upon which they start to proliferate and generate effector cells to initiate a functional immune response. Metabolic reprogramming is essential to meet the biosynthetic demands of the differentiation process, and failure to do so can promote the development of hypofunctional exhausted T cells.IntroductionNaïve T cells remain in an actively maintained state of quiescence until activation by antigenic signals, upon which they start to proliferate and generate effector cells to initiate a functional immune response. Metabolic reprogramming is essential to meet the biosynthetic demands of the differentiation process, and failure to do so can promote the development of hypofunctional exhausted T cells.Here we used 13C metabolomics and transcriptomics to study the metabolism of CD8+ T cells in their complete course of differentiation from naïve over stem-like memory to effector cells and in exhaustion-inducing conditions.MethodsHere we used 13C metabolomics and transcriptomics to study the metabolism of CD8+ T cells in their complete course of differentiation from naïve over stem-like memory to effector cells and in exhaustion-inducing conditions.The quiescence of naïve T cells was evident in a profound suppression of glucose oxidation and a decreased expression of ENO1, downstream of which no glycolytic flux was detectable. Moreover, TCA cycle activity was low in naïve T cells and associated with a downregulation of SDH subunits. Upon stimulation and exit from quiescence, the initiation of cell growth and proliferation was accompanied by differential expression of metabolic enzymes and metabolic reprogramming towards aerobic glycolysis with high rates of nutrient uptake, respiration and lactate production. High flux in anabolic pathways imposed a strain on NADH homeostasis, which coincided with engagement of the proline cycle for mitochondrial redox shuttling. With acquisition of effector functions, cells increasingly relied on glycolysis as opposed to oxidative phosphorylation, which was, however, not linked to changes in mitochondrial abundance. In exhaustion, decreased effector function concurred with a reduction in mitochondrial metabolism, glycolysis and amino acid import, and an upregulation of quiescence-associated genes, TXNIP and KLF2, and the T cell suppressive metabolites succinate and itaconate.ResultsThe quiescence of naïve T cells was evident in a profound suppression of glucose oxidation and a decreased expression of ENO1, downstream of which no glycolytic flux was detectable. Moreover, TCA cycle activity was low in naïve T cells and associated with a downregulation of SDH subunits. Upon stimulation and exit from quiescence, the initiation of cell growth and proliferation was accompanied by differential expression of metabolic enzymes and metabolic reprogramming towards aerobic glycolysis with high rates of nutrient uptake, respiration and lactate production. High flux in anabolic pathways imposed a strain on NADH homeostasis, which coincided with engagement of the proline cycle for mitochondrial redox shuttling. With acquisition of effector functions, cells increasingly relied on glycolysis as opposed to oxidative phosphorylation, which was, however, not linked to changes in mitochondrial abundance. In exhaustion, decreased effector function concurred with a reduction in mitochondrial metabolism, glycolysis and amino acid import, and an upregulation of quiescence-associated genes, TXNIP and KLF2, and the T cell suppressive metabolites succinate and itaconate.Overall, these results identify multiple metabolic features that regulate quiescence, proliferation and effector function, but also exhaustion of CD8+ T cells during differentiation. Thus, targeting these metabolic checkpoints may be a promising therapeutic strategy for both prevention of exhaustion and promotion of stemness of anti-tumor T cells.DiscussionOverall, these results identify multiple metabolic features that regulate quiescence, proliferation and effector function, but also exhaustion of CD8+ T cells during differentiation. Thus, targeting these metabolic checkpoints may be a promising therapeutic strategy for both prevention of exhaustion and promotion of stemness of anti-tumor T cells. |
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| AbstractList | IntroductionNaïve T cells remain in an actively maintained state of quiescence until activation by antigenic signals, upon which they start to proliferate and generate effector cells to initiate a functional immune response. Metabolic reprogramming is essential to meet the biosynthetic demands of the differentiation process, and failure to do so can promote the development of hypofunctional exhausted T cells.MethodsHere we used 13C metabolomics and transcriptomics to study the metabolism of CD8+ T cells in their complete course of differentiation from naïve over stem-like memory to effector cells and in exhaustion-inducing conditions. ResultsThe quiescence of naïve T cells was evident in a profound suppression of glucose oxidation and a decreased expression of ENO1, downstream of which no glycolytic flux was detectable. Moreover, TCA cycle activity was low in naïve T cells and associated with a downregulation of SDH subunits. Upon stimulation and exit from quiescence, the initiation of cell growth and proliferation was accompanied by differential expression of metabolic enzymes and metabolic reprogramming towards aerobic glycolysis with high rates of nutrient uptake, respiration and lactate production. High flux in anabolic pathways imposed a strain on NADH homeostasis, which coincided with engagement of the proline cycle for mitochondrial redox shuttling. With acquisition of effector functions, cells increasingly relied on glycolysis as opposed to oxidative phosphorylation, which was, however, not linked to changes in mitochondrial abundance. In exhaustion, decreased effector function concurred with a reduction in mitochondrial metabolism, glycolysis and amino acid import, and an upregulation of quiescence-associated genes, TXNIP and KLF2, and the T cell suppressive metabolites succinate and itaconate. DiscussionOverall, these results identify multiple metabolic features that regulate quiescence, proliferation and effector function, but also exhaustion of CD8+ T cells during differentiation. Thus, targeting these metabolic checkpoints may be a promising therapeutic strategy for both prevention of exhaustion and promotion of stemness of anti-tumor T cells. Naïve T cells remain in an actively maintained state of quiescence until activation by antigenic signals, upon which they start to proliferate and generate effector cells to initiate a functional immune response. Metabolic reprogramming is essential to meet the biosynthetic demands of the differentiation process, and failure to do so can promote the development of hypofunctional exhausted T cells.IntroductionNaïve T cells remain in an actively maintained state of quiescence until activation by antigenic signals, upon which they start to proliferate and generate effector cells to initiate a functional immune response. Metabolic reprogramming is essential to meet the biosynthetic demands of the differentiation process, and failure to do so can promote the development of hypofunctional exhausted T cells.Here we used 13C metabolomics and transcriptomics to study the metabolism of CD8+ T cells in their complete course of differentiation from naïve over stem-like memory to effector cells and in exhaustion-inducing conditions.MethodsHere we used 13C metabolomics and transcriptomics to study the metabolism of CD8+ T cells in their complete course of differentiation from naïve over stem-like memory to effector cells and in exhaustion-inducing conditions.The quiescence of naïve T cells was evident in a profound suppression of glucose oxidation and a decreased expression of ENO1, downstream of which no glycolytic flux was detectable. Moreover, TCA cycle activity was low in naïve T cells and associated with a downregulation of SDH subunits. Upon stimulation and exit from quiescence, the initiation of cell growth and proliferation was accompanied by differential expression of metabolic enzymes and metabolic reprogramming towards aerobic glycolysis with high rates of nutrient uptake, respiration and lactate production. High flux in anabolic pathways imposed a strain on NADH homeostasis, which coincided with engagement of the proline cycle for mitochondrial redox shuttling. With acquisition of effector functions, cells increasingly relied on glycolysis as opposed to oxidative phosphorylation, which was, however, not linked to changes in mitochondrial abundance. In exhaustion, decreased effector function concurred with a reduction in mitochondrial metabolism, glycolysis and amino acid import, and an upregulation of quiescence-associated genes, TXNIP and KLF2, and the T cell suppressive metabolites succinate and itaconate.ResultsThe quiescence of naïve T cells was evident in a profound suppression of glucose oxidation and a decreased expression of ENO1, downstream of which no glycolytic flux was detectable. Moreover, TCA cycle activity was low in naïve T cells and associated with a downregulation of SDH subunits. Upon stimulation and exit from quiescence, the initiation of cell growth and proliferation was accompanied by differential expression of metabolic enzymes and metabolic reprogramming towards aerobic glycolysis with high rates of nutrient uptake, respiration and lactate production. High flux in anabolic pathways imposed a strain on NADH homeostasis, which coincided with engagement of the proline cycle for mitochondrial redox shuttling. With acquisition of effector functions, cells increasingly relied on glycolysis as opposed to oxidative phosphorylation, which was, however, not linked to changes in mitochondrial abundance. In exhaustion, decreased effector function concurred with a reduction in mitochondrial metabolism, glycolysis and amino acid import, and an upregulation of quiescence-associated genes, TXNIP and KLF2, and the T cell suppressive metabolites succinate and itaconate.Overall, these results identify multiple metabolic features that regulate quiescence, proliferation and effector function, but also exhaustion of CD8+ T cells during differentiation. Thus, targeting these metabolic checkpoints may be a promising therapeutic strategy for both prevention of exhaustion and promotion of stemness of anti-tumor T cells.DiscussionOverall, these results identify multiple metabolic features that regulate quiescence, proliferation and effector function, but also exhaustion of CD8+ T cells during differentiation. Thus, targeting these metabolic checkpoints may be a promising therapeutic strategy for both prevention of exhaustion and promotion of stemness of anti-tumor T cells. |
| Author | Ghesquière, Bart Zippelius, Alfred Trefny, Marcel Nemati, Niloofar Lamberti, Giorgia Schumacher, Petra Krogsdam, Anne Sandbichler, Adolf Kirchmair, Alexander Sopper, Sieghart Siller, Anita Trajanoski, Zlatko Hörtnagl, Paul |
| AuthorAffiliation | 3 NGS Core Facility, Biocenter, Medical University of Innsbruck , Innsbruck , Austria 6 Institute of Zoology, University of Innsbruck , Innsbruck , Austria 8 Metabolomics Core Facility Leuven, Center for Cancer Biology, VIB , Leuven , Belgium 1 Institute of Bioinformatics, Biocenter, Medical University of Innsbruck , Innsbruck , Austria 4 Central Institute for Blood Transfusion and Immunology, Tirol Kliniken GmbH , Innsbruck , Austria 5 Core Facility FACS Sorting, University Clinic for Internal Medicine V, Medical University of Innsbruck , Innsbruck , Austria 7 Laboratory of Applied Mass Spectrometry, Department of Cellular and Molecular Medicine, KU Leuven , Leuven , Belgium 2 Department of Biomedicine, Cancer Immunology, University and University Hospital of Basel , Basel , Switzerland |
| AuthorAffiliation_xml | – name: 1 Institute of Bioinformatics, Biocenter, Medical University of Innsbruck , Innsbruck , Austria – name: 8 Metabolomics Core Facility Leuven, Center for Cancer Biology, VIB , Leuven , Belgium – name: 2 Department of Biomedicine, Cancer Immunology, University and University Hospital of Basel , Basel , Switzerland – name: 4 Central Institute for Blood Transfusion and Immunology, Tirol Kliniken GmbH , Innsbruck , Austria – name: 5 Core Facility FACS Sorting, University Clinic for Internal Medicine V, Medical University of Innsbruck , Innsbruck , Austria – name: 3 NGS Core Facility, Biocenter, Medical University of Innsbruck , Innsbruck , Austria – name: 7 Laboratory of Applied Mass Spectrometry, Department of Cellular and Molecular Medicine, KU Leuven , Leuven , Belgium – name: 6 Institute of Zoology, University of Innsbruck , Innsbruck , Austria |
| Author_xml | – sequence: 1 givenname: Alexander surname: Kirchmair fullname: Kirchmair, Alexander – sequence: 2 givenname: Niloofar surname: Nemati fullname: Nemati, Niloofar – sequence: 3 givenname: Giorgia surname: Lamberti fullname: Lamberti, Giorgia – sequence: 4 givenname: Marcel surname: Trefny fullname: Trefny, Marcel – sequence: 5 givenname: Anne surname: Krogsdam fullname: Krogsdam, Anne – sequence: 6 givenname: Anita surname: Siller fullname: Siller, Anita – sequence: 7 givenname: Paul surname: Hörtnagl fullname: Hörtnagl, Paul – sequence: 8 givenname: Petra surname: Schumacher fullname: Schumacher, Petra – sequence: 9 givenname: Sieghart surname: Sopper fullname: Sopper, Sieghart – sequence: 10 givenname: Adolf surname: Sandbichler fullname: Sandbichler, Adolf – sequence: 11 givenname: Alfred surname: Zippelius fullname: Zippelius, Alfred – sequence: 12 givenname: Bart surname: Ghesquière fullname: Ghesquière, Bart – sequence: 13 givenname: Zlatko surname: Trajanoski fullname: Trajanoski, Zlatko |
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| CitedBy_id | crossref_primary_10_1007_s10528_023_10646_9 crossref_primary_10_3390_cancers16132290 crossref_primary_10_1016_j_freeradbiomed_2025_05_395 crossref_primary_10_1158_0008_5472_CAN_23_1489 crossref_primary_10_1038_s41420_025_02397_w crossref_primary_10_3389_fcell_2024_1416472 |
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| Copyright | Copyright © 2023 Kirchmair, Nemati, Lamberti, Trefny, Krogsdam, Siller, Hörtnagl, Schumacher, Sopper, Sandbichler, Zippelius, Ghesquière and Trajanoski. Copyright © 2023 Kirchmair, Nemati, Lamberti, Trefny, Krogsdam, Siller, Hörtnagl, Schumacher, Sopper, Sandbichler, Zippelius, Ghesquière and Trajanoski 2023 Kirchmair, Nemati, Lamberti, Trefny, Krogsdam, Siller, Hörtnagl, Schumacher, Sopper, Sandbichler, Zippelius, Ghesquière and Trajanoski |
| Copyright_xml | – notice: Copyright © 2023 Kirchmair, Nemati, Lamberti, Trefny, Krogsdam, Siller, Hörtnagl, Schumacher, Sopper, Sandbichler, Zippelius, Ghesquière and Trajanoski. – notice: Copyright © 2023 Kirchmair, Nemati, Lamberti, Trefny, Krogsdam, Siller, Hörtnagl, Schumacher, Sopper, Sandbichler, Zippelius, Ghesquière and Trajanoski 2023 Kirchmair, Nemati, Lamberti, Trefny, Krogsdam, Siller, Hörtnagl, Schumacher, Sopper, Sandbichler, Zippelius, Ghesquière and Trajanoski |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by: Xiong Li, Huazhong University of Science and Technology, China Reviewed by: Adam Klocperk, Charles University, Czechia; Guang Sheng Ling, The University of Hong Kong, Hong Kong SAR, China Present address: Marcel Trefny, Division of Clinical Pharmacology, Ludwig-Maximilians-Universität München, Munich, Germany These authors share first authorship |
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