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Quantitative genome-scale metabolic modeling of human CD4+ T cell differentiation reveals subset-specific regulation of glycosphingolipid pathways
Örebro University, School of Medical Sciences. Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.ORCID iD: 0000-0003-0475-2763
Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
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2021 (English)In: Cell Reports, E-ISSN 2211-1247, Vol. 37, no 6, article id 109973Article in journal (Refereed) Published
Abstract [en]

T cell activation, proliferation, and differentiation involve metabolic reprogramming resulting from the interplay of genes, proteins, and metabolites. Here, we aim to understand the metabolic pathways involved in the activation and functional differentiation of human CD4+ T cell subsets (T helper [Th]1, Th2, Th17, and induced regulatory T [iTreg] cells). Here, we combine genome-scale metabolic modeling, gene expression data, and targeted and non-targeted lipidomics experiments, together with in vitro gene knockdown experiments, and show that human CD4+ T cells undergo specific metabolic changes during activation and functional differentiation. In addition, we confirm the importance of ceramide and glycosphingolipid biosynthesis pathways in Th17 differentiation and effector functions. Through in vitro gene knockdown experiments, we substantiate the requirement of serine palmitoyltransferase (SPT), a de novo sphingolipid pathway in the expression of proinflammatory cytokines (interleukin [IL]-17A and IL17F) by Th17 cells. Our findings provide a comprehensive resource for selective manipulation of CD4+ T cells under disease conditions characterized by an imbalance of Th17/natural Treg (nTreg) cells.

Place, publisher, year, edition, pages
Cell Press , 2021. Vol. 37, no 6, article id 109973
Keywords [en]
CD4(+) T cells, ceramides, gene expression, genome-scale metabolic modeling, glycosphingolipid metabolism, lipid metabolism, lipidomics, metabolic pathways, sphingolipids, type 1 diabetes
National Category
Immunology in the medical area
Identifiers
URN: urn:nbn:se:oru:diva-95400DOI: 10.1016/j.celrep.2021.109973ISI: 000718275500009PubMedID: 34758307Scopus ID: 2-s2.0-85118862025OAI: oai:DiVA.org:oru-95400DiVA, id: diva2:1610879
Funder
Novo Nordisk, NNF18OC0034506 NNF19OC0057418Academy of Finland, 333981 292335European Commission
Note

Funding agencies:

Academy of Finland Centre of Excellence in Molecular Systems Immunology and Physiology Research (SyMMyS) 250114

Sigrid Juselius Foundation

Jane and Aatos Erkko Foundation

Finnish Cancer Foundation

Juvenile Diabetes Research Foundation 2-SRA-2014-159-Q-R

Available from: 2021-11-12 Created: 2021-11-12 Last updated: 2024-01-17Bibliographically approved

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Sen, ParthoHyötyläinen, TuuliaOresic, Matej

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