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

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

Nature Communications, Volume: 10, Issue: 1

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

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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
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa49646
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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-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.
Keywords: T cells, metabolism, glutamine, STAT5, TCA cycle
College: Faculty of Medicine, Health and Life Sciences
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). D.K.F. is supported by Science Foundation Ireland (13/CDA/2161).
Issue: 1