Abstract
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+ Tcell 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 invitro gene knockdown experiments, and show that human CD4+ Tcells 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 invitro 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+ Tcells under disease conditions characterized by an imbalance of Th17/natural Treg (nTreg) cells.
Highlights
CD4+ T cells orchestrate immune responses and mediate protective immunity against pathogens (Zhu and Paul, 2008)
We reveal the essentiality of glycosphingolipid (GSL) pathways in Th17 cells and show that the sphingolipid metabolic pathways were altered in the CD4+ T cells (Kallionpaaet al., 2019) and peripheral blood mononuclear cells (PBMCs) (Kallionpaaet al., 2019; Sen et al, 2020) of the children who developed islet autoantibodies
Identification of metabolic genes (MGs) of human CD4+ T cell activation and subset differentiation When mapping the published gene expression data of each CD4+ T cell subset (i.e., the lipidome of resting naive (Thp), Th1, and Th2 [Kanduri et al, 2015], Th17 [Tuomela et al, 2016], and induced Treg (iTreg) cells [Ubaid Ullah et al, 2018]) to the various available human metabolic reconstructions and pathway databases, we found that approximately 17% of the genes expressed in each CD4+ T cell subset were found in the human metabolic reaction (HMR2) (Mardinoglu et al, 2014) database, while only $5% of the genes were found in the Kyoto Encyclopedia of Genes and Genomes (KEGG) (Kanehisa and Goto, 2000) and the Encyclopedia of Human Genes and Metabolism (HumanCyc) (Trupp et al, 2010) pathway databases (Figure S1)
Summary
CD4+ T cells orchestrate immune responses and mediate protective immunity against pathogens (Zhu and Paul, 2008). T cells undergo metabolic reprogramming in order to provide energy and biosynthetic intermediates for growth and effector functions (Buck et al, 2015; Chang and Pearce, 2016; MacIver et al, 2013; Pearce and Pearce, 2013; Sugiura and Rathmell, 2018). At this stage, aerobic glycolysis is augmented (the Warburg effect), which increases the activities of glycolytic enzymes. Activated T cells induces a metabolic sensor, i.e., mammalian target of rapamycin (mTOR), to either differentiate into Teff cells or become suppressive Treg cells (Barbi et al, 2013). mTOR signaling induces the transcription factors Myc and HIF-1a, driving the expression of genes important for glycolysis and glutaminolysis as well as regulating STAT signaling for T cell differentiation (Powell and Delgoffe, 2010)
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