Akt and STAT5 mediate naïve human CD4+ T-cell early metabolic response to TCR stimulation

Jones, Nick; Vincent, Emma E.; Cronin, James; Panetti, Silvia; Chambers, Megan; Holm, Sean R.; Owens, Sian-eleri; Francis, Nigel; Finlay, David K.; Thornton, Cathy

doi:10.1038/s41467-019-10023-4

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Akt and STAT5 mediate naïve human CD4+ T-cell early metabolic response to TCR stimulation

Nick Jones

, Emma E. Vincent

, James Cronin

, Silvia Panetti

, Megan Chambers, Sean R. Holm, Sian-eleri Owens

, Nigel Francis, David K. Finlay

, Cathy Thornton

Nature Communications, Volume: 10, Issue: 1

Swansea University Authors: Nick Jones , James Cronin , Sian-eleri Owens , Nigel Francis, Cathy Thornton

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DOI (Published version): 10.1038/s41467-019-10023-4

Abstract

Metabolic pathways that regulate T-cell function show promise as therapeutic targets in diverse diseases. Here, we show that at rest cultured human effector memory and central memory CD4+ T-cells have elevated levels of glycolysis and oxidative phosphorylation (OXPHOS), in comparison to naïve T-cell...

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Published in:	Nature Communications
ISSN:	2041-1723
Published:	Springer Science and Business Media LLC 2019
Online Access:	Check full text
URI:	https://cronfa.swan.ac.uk/Record/cronfa49646
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first_indexed	2019-03-20T13:59:11Z
last_indexed	2023-01-11T14:25:53Z
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Here, we show that at rest cultured human effector memory and central memory CD4+ T-cells have elevated levels of glycolysis and oxidative phosphorylation (OXPHOS), in comparison to naïve T-cells. Despite having low resting metabolic rates, naive T-cells respond to TCR stimulation with robust and rapid increases in glycolysis and OXPHOS. This early metabolic switch requires Akt activity to support increased rates of glycolysis and STAT5 activity for amino acid biosynthesis and TCA cycle anaplerosis. Importantly, both STAT5 inhibition and disruption of TCA cycle anaplerosis are associated with reduced IL-2 production, demonstrating the functional importance of this early metabolic program. Our results define STAT5 as a key node in modulating the early metabolic program following activation in naive CD4+ T-cells and in turn provide greater understanding of how cellular metabolism shapes T-cell responses.</abstract><type>Journal Article</type><journal>Nature Communications</journal><volume>10</volume><journalNumber>1</journalNumber><paginationStart/><paginationEnd/><publisher>Springer Science and Business Media LLC</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic>2041-1723</issnElectronic><keywords>T cells, metabolism, glutamine, STAT5, TCA cycle</keywords><publishedDay>3</publishedDay><publishedMonth>5</publishedMonth><publishedYear>2019</publishedYear><publishedDate>2019-05-03</publishedDate><doi>10.1038/s41467-019-10023-4</doi><url/><notes/><college>COLLEGE NANME</college><department>Biomedical Sciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>BMS</DepartmentCode><institution>Swansea University</institution><apcterm/><funders>We thank D. Avizonis and L. Choinière from McGill University Metabolomics Core Facility, J. Rathmell, J. Blagih and D. Elder for useful discussion, S. James for assistance with confocal microscopy, D. Rees for assistance with ImageJ, staff in the Swansea University Joint Clinical Research Facility for phlebotomy, and all blood donors. This work was supported with grants awarded by Saint David’s Medical Foundation (SDMF), Life Sciences Research Network Wales (NRN). S.P. was supported by a Wellcome Trust Biomedical Vacation Scholarship. E.E.V. was supported by CRUK (C18281/A19169) and is now supported by a Diabetes UK RD Lawrence Fellowship (17/0005587). 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spelling	2022-12-06T15:13:02.1805654 v2 49646 2019-03-20 Akt and STAT5 mediate naïve human CD4+ T-cell early metabolic response to TCR stimulation 0fce0f7ddbdbfeb968f4e2f1e3f86744 0000-0003-4846-5117 Nick Jones Nick Jones true false 9cfd17551c0d1f7438895121e4fbb6e8 0000-0002-0590-9462 James Cronin James Cronin true false 721deb4604d122019244cfdf08820cbe 0000-0003-1806-5235 Sian-eleri Owens Sian-eleri Owens true false a726d297bbed7e5cd4c320f8f9dbf4d7 Nigel Francis Nigel Francis true false c71a7a4be7361094d046d312202bce0c 0000-0002-5153-573X Cathy Thornton Cathy Thornton true false 2019-03-20 BMS Metabolic pathways that regulate T-cell function show promise as therapeutic targets in diverse diseases. Here, we show that at rest cultured human effector memory and central memory CD4+ T-cells have elevated levels of glycolysis and oxidative phosphorylation (OXPHOS), in comparison to naïve T-cells. Despite having low resting metabolic rates, naive T-cells respond to TCR stimulation with robust and rapid increases in glycolysis and OXPHOS. This early metabolic switch requires Akt activity to support increased rates of glycolysis and STAT5 activity for amino acid biosynthesis and TCA cycle anaplerosis. Importantly, both STAT5 inhibition and disruption of TCA cycle anaplerosis are associated with reduced IL-2 production, demonstrating the functional importance of this early metabolic program. Our results define STAT5 as a key node in modulating the early metabolic program following activation in naive CD4+ T-cells and in turn provide greater understanding of how cellular metabolism shapes T-cell responses. Journal Article Nature Communications 10 1 Springer Science and Business Media LLC 2041-1723 T cells, metabolism, glutamine, STAT5, TCA cycle 3 5 2019 2019-05-03 10.1038/s41467-019-10023-4 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University We thank D. Avizonis and L. Choinière from McGill University Metabolomics Core Facility, J. Rathmell, J. Blagih and D. Elder for useful discussion, S. James for assistance with confocal microscopy, D. Rees for assistance with ImageJ, staff in the Swansea University Joint Clinical Research Facility for phlebotomy, and all blood donors. This work was supported with grants awarded by Saint David’s Medical Foundation (SDMF), Life Sciences Research Network Wales (NRN). S.P. was supported by a Wellcome Trust Biomedical Vacation Scholarship. E.E.V. was supported by CRUK (C18281/A19169) and is now supported by a Diabetes UK RD Lawrence Fellowship (17/0005587). D.K.F. is supported by Science Foundation Ireland (13/CDA/2161). 2022-12-06T15:13:02.1805654 2019-03-20T11:26:13.3675346 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Nick Jones 0000-0003-4846-5117 1 Emma E. Vincent 0000-0002-8917-7384 2 James Cronin 0000-0002-0590-9462 3 Silvia Panetti 0000-0003-0176-7636 4 Megan Chambers 5 Sean R. Holm 6 Sian-eleri Owens 0000-0003-1806-5235 7 Nigel Francis 8 David K. Finlay 0000-0003-2716-6679 9 Cathy Thornton 0000-0002-5153-573X 10 0049646-08052019110646.pdf 49646.pdf 2019-05-08T11:06:46.3370000 Output 1378587 application/pdf Version of Record true 2019-05-08T00:00:00.0000000 Released under the terms of a Creative Commons Attribution 4.0 International license (CC-BY). true eng
title	Akt and STAT5 mediate naïve human CD4+ T-cell early metabolic response to TCR stimulation
spellingShingle	Akt and STAT5 mediate naïve human CD4+ T-cell early metabolic response to TCR stimulation Nick Jones James Cronin Sian-eleri Owens Nigel Francis Cathy Thornton
title_short	Akt and STAT5 mediate naïve human CD4+ T-cell early metabolic response to TCR stimulation
title_full	Akt and STAT5 mediate naïve human CD4+ T-cell early metabolic response to TCR stimulation
title_fullStr	Akt and STAT5 mediate naïve human CD4+ T-cell early metabolic response to TCR stimulation
title_full_unstemmed	Akt and STAT5 mediate naïve human CD4+ T-cell early metabolic response to TCR stimulation
title_sort	Akt and STAT5 mediate naïve human CD4+ T-cell early metabolic response to TCR stimulation
author_id_str_mv	0fce0f7ddbdbfeb968f4e2f1e3f86744 9cfd17551c0d1f7438895121e4fbb6e8 721deb4604d122019244cfdf08820cbe a726d297bbed7e5cd4c320f8f9dbf4d7 c71a7a4be7361094d046d312202bce0c
author_id_fullname_str_mv	0fce0f7ddbdbfeb968f4e2f1e3f86744_*_Nick Jones 9cfd17551c0d1f7438895121e4fbb6e8__James Cronin 721deb4604d122019244cfdf08820cbe__Sian-eleri Owens a726d297bbed7e5cd4c320f8f9dbf4d7__Nigel Francis c71a7a4be7361094d046d312202bce0c_**_Cathy Thornton
author	Nick Jones James Cronin Sian-eleri Owens Nigel Francis Cathy Thornton
author2	Nick Jones Emma E. Vincent James Cronin Silvia Panetti Megan Chambers Sean R. Holm Sian-eleri Owens Nigel Francis David K. Finlay Cathy Thornton
format	Journal article
container_title	Nature Communications
container_volume	10
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publishDate	2019
institution	Swansea University
issn	2041-1723
doi_str_mv	10.1038/s41467-019-10023-4
publisher	Springer Science and Business Media LLC
college_str	Faculty of Medicine, Health and Life Sciences
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hierarchy_top_title	Faculty of Medicine, Health and Life Sciences
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hierarchy_parent_title	Faculty of Medicine, Health and Life Sciences
department_str	Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
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description	Metabolic pathways that regulate T-cell function show promise as therapeutic targets in diverse diseases. Here, we show that at rest cultured human effector memory and central memory CD4+ T-cells have elevated levels of glycolysis and oxidative phosphorylation (OXPHOS), in comparison to naïve T-cells. Despite having low resting metabolic rates, naive T-cells respond to TCR stimulation with robust and rapid increases in glycolysis and OXPHOS. This early metabolic switch requires Akt activity to support increased rates of glycolysis and STAT5 activity for amino acid biosynthesis and TCA cycle anaplerosis. Importantly, both STAT5 inhibition and disruption of TCA cycle anaplerosis are associated with reduced IL-2 production, demonstrating the functional importance of this early metabolic program. Our results define STAT5 as a key node in modulating the early metabolic program following activation in naive CD4+ T-cells and in turn provide greater understanding of how cellular metabolism shapes T-cell responses.
published_date	2019-05-03T04:00:49Z
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Akt and STAT5 mediate naïve human CD4+ T-cell early metabolic response to TCR stimulation

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