Quantitative genome-scale metabolic modeling of human CD4+ T cell differentiation reveals subset-specific regulation of glycosphingolipid pathways

Abstract

<p>T cell activation, proliferation, and differentiation involve metabolic reprogramming resulting from the interplay of genes, <a href="https://www.sciencedirect.com/topics/neuroscience/proteome" title="Learn more about proteins from ScienceDirect's AI-generated Topic Pages">proteins</a>, and metabolites. Here, we aim to understand the <a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/metabolic-pathways" title="Learn more about metabolic pathways from ScienceDirect's AI-generated Topic Pages">metabolic pathways</a> 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 <a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/lipidomics" title="Learn more about lipidomics from ScienceDirect's AI-generated Topic Pages">lipidomics</a> experiments, together with <em>in vitro</em> <a href="https://www.sciencedirect.com/topics/immunology-and-microbiology/gene-knockdown" title="Learn more about gene knockdown from ScienceDirect's AI-generated Topic Pages">gene knockdown</a> experiments, and show that human CD4⁺ T cells undergo specific metabolic changes during activation and functional differentiation. In addition, we confirm the importance of <a href="https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/ceramide" title="Learn more about ceramide from ScienceDirect's AI-generated Topic Pages">ceramide</a> and <a href="https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/glycosphingolipid" title="Learn more about glycosphingolipid from ScienceDirect's AI-generated Topic Pages">glycosphingolipid</a> <a href="https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/anabolism" title="Learn more about biosynthesis from ScienceDirect's AI-generated Topic Pages">biosynthesis</a> pathways in Th17 differentiation and effector functions. Through <em>in vitro</em> gene knockdown experiments, we substantiate the requirement of <a href="https://www.sciencedirect.com/topics/neuroscience/serine-palmitoyltransferase" title="Learn more about serine palmitoyltransferase from ScienceDirect's AI-generated Topic Pages">serine palmitoyltransferase</a> (<em>SPT</em>), a <em>de novo</em> <a href="https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/sphingolipid" title="Learn more about sphingolipid from ScienceDirect's AI-generated Topic Pages">sphingolipid</a> pathway in the expression of <a href="https://www.sciencedirect.com/topics/immunology-and-microbiology/proinflammatory-cytokine" title="Learn more about proinflammatory cytokines from ScienceDirect's AI-generated Topic Pages">proinflammatory cytokines</a> (interleukin [IL]-17A and IL17F) by <a href="https://www.sciencedirect.com/topics/immunology-and-microbiology/th17-cell" title="Learn more about Th17 cells from ScienceDirect's AI-generated Topic Pages">Th17 cells</a>. 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.</p>