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Akt and STAT5 mediate naïve human CD4+ T-cell early metabolic response to TCR stimulation / James, Cronin; Sian-eleri, Owens; Nigel, Francis; Catherine, Thornton; Nicholas, Jones

Nature Communications, Volume: 10, Issue: 1

Swansea University Authors: James, Cronin, Sian-eleri, Owens, Nigel, Francis, Catherine, Thornton, Nicholas, Jones

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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
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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><publisher>Springer Science and Business Media LLC</publisher><issnElectronic>2041-1723</issnElectronic><keywords>T cells, metabolism, glutamine, STAT5, TCA cycle</keywords><publishedDay>1</publishedDay><publishedMonth>12</publishedMonth><publishedYear>2019</publishedYear><publishedDate>2019-12-01</publishedDate><doi>10.1038/s41467-019-10023-4</doi><url>http://dx.doi.org/10.1038/s41467-019-10023-4</url><notes/><college>COLLEGE NANME</college><department>Biomedical Sciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>BMS</DepartmentCode><institution>Swansea University</institution><lastEdited>2020-08-06T15:19:52.8137734</lastEdited><Created>2019-03-20T11:26:13.3675346</Created><authors><author><firstname>Emma E.</firstname><surname>Vincent</surname><order>1</order></author><author><firstname>James</firstname><surname>Cronin</surname><orcid>0000-0002-0590-9462</orcid><order>2</order></author><author><firstname>Silvia</firstname><surname>Panetti</surname><order>3</order></author><author><firstname>Megan</firstname><surname>Chambers</surname><order>4</order></author><author><firstname>Sean R.</firstname><surname>Holm</surname><order>5</order></author><author><firstname>Sian-eleri</firstname><surname>Owens</surname><orcid>0000-0003-1806-5235</orcid><order>6</order></author><author><firstname>Nigel</firstname><surname>Francis</surname><orcid>0000-0002-4706-4795</orcid><order>7</order></author><author><firstname>David K.</firstname><surname>Finlay</surname><order>8</order></author><author><firstname>Catherine</firstname><surname>Thornton</surname><orcid>0000-0002-5153-573X</orcid><order>9</order></author><author><firstname>Nicholas</firstname><surname>Jones</surname><orcid>0000-0003-4846-5117</orcid><order>10</order></author></authors><documents><document><filename>0049646-08052019110646.pdf</filename><originalFilename>49646.pdf</originalFilename><uploaded>2019-05-08T11:06:46.3370000</uploaded><type>Output</type><contentLength>1378587</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><action/><embargoDate>2019-05-08T00:00:00.0000000</embargoDate><documentNotes>Released under the terms of a Creative Commons Attribution 4.0 International license (CC-BY).</documentNotes><copyrightCorrect>true</copyrightCorrect><language>eng</language></document></documents><OutputDurs/></rfc1807>
spelling v2 49646 2019-03-20 Akt and STAT5 mediate naïve human CD4+ T-cell early metabolic response to TCR stimulation 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 0000-0002-4706-4795 Nigel Francis Nigel Francis true false c71a7a4be7361094d046d312202bce0c 0000-0002-5153-573X Catherine Thornton Catherine Thornton true false 0fce0f7ddbdbfeb968f4e2f1e3f86744 0000-0003-4846-5117 Nicholas Jones Nicholas Jones 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 1 12 2019 2019-12-01 10.1038/s41467-019-10023-4 http://dx.doi.org/10.1038/s41467-019-10023-4 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University 2020-08-06T15:19:52.8137734 2019-03-20T11:26:13.3675346 Emma E. Vincent 1 James Cronin 0000-0002-0590-9462 2 Silvia Panetti 3 Megan Chambers 4 Sean R. Holm 5 Sian-eleri Owens 0000-0003-1806-5235 6 Nigel Francis 0000-0002-4706-4795 7 David K. Finlay 8 Catherine Thornton 0000-0002-5153-573X 9 Nicholas Jones 0000-0003-4846-5117 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
James, Cronin
Sian-eleri, Owens
Nigel, Francis
Catherine, Thornton
Nicholas, Jones
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 9cfd17551c0d1f7438895121e4fbb6e8
721deb4604d122019244cfdf08820cbe
a726d297bbed7e5cd4c320f8f9dbf4d7
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author_id_fullname_str_mv 9cfd17551c0d1f7438895121e4fbb6e8_***_James, Cronin
721deb4604d122019244cfdf08820cbe_***_Sian-eleri, Owens
a726d297bbed7e5cd4c320f8f9dbf4d7_***_Nigel, Francis
c71a7a4be7361094d046d312202bce0c_***_Catherine, Thornton
0fce0f7ddbdbfeb968f4e2f1e3f86744_***_Nicholas, Jones
author James, Cronin
Sian-eleri, Owens
Nigel, Francis
Catherine, Thornton
Nicholas, Jones
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
url http://dx.doi.org/10.1038/s41467-019-10023-4
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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 2019-12-01T15:19:49Z
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