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

Autor:	Jones N; Institute of Life Science, Swansea University Medical School, Swansea, SA2 8PP, UK., Vincent EE; MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Bristol, BS8 2BN, UK.; Cellular and Molecular Medicine, University of Bristol, Biomedical Sciences Building, Bristol, BS8 1TD, UK., Cronin JG; Institute of Life Science, Swansea University Medical School, Swansea, SA2 8PP, UK., Panetti S; Institute of Life Science, Swansea University Medical School, Swansea, SA2 8PP, UK., Chambers M; Institute of Life Science, Swansea University Medical School, Swansea, SA2 8PP, UK., Holm SR; Institute of Life Science, Swansea University Medical School, Swansea, SA2 8PP, UK., Owens SE; Institute of Life Science, Swansea University Medical School, Swansea, SA2 8PP, UK., Francis NJ; Institute of Life Science, Swansea University Medical School, Swansea, SA2 8PP, UK., Finlay DK; School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearce Street, Dublin, Ireland.; School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearce Street, Dublin, Ireland., Thornton CA; Institute of Life Science, Swansea University Medical School, Swansea, SA2 8PP, UK. c.a.thornton@swansea.ac.uk.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2019 May 03; Vol. 10 (1), pp. 2042. Date of Electronic Publication: 2019 May 03.
DOI:	10.1038/s41467-019-10023-4
Abstrakt:	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.
Databáze:	MEDLINE
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