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

Sen, Partho; Andrabi, Syed Bilal Ahmad; Buchacher, Tanja; Khan, Mohd Moin; Kalim, Ubaid Ullah; Lindeman, Tuomas; Alves, Marina Amaral; Hinkkanen, Victoria; Kemppainen, Esko; Dickens, Alex M.; Rasool, Omid; Hyötyläinen, Tuulia; Lahesmaa, Riitta; Orešič, Matej

doi:10.1016/j.celrep.2021.109973

Cited by 13 publications

(10 citation statements)

References 84 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Further, the role of sphingolipid metabolism in T helper differentiation and function is still emerging. A recent report on a genome-scale metabolic modeling of human CD4 + T cells has documented a role for the SPT complex in T H 17 cell cytokine production; however, the molecular details were undefined ( 40 ). Another study showed the importance of ceramide accumulation in T reg cell function ( 81 ).…”

Section: Discussionmentioning

confidence: 99%

“…Although the role of sphingolipids synthesized via de novo pathway is appreciated in many cellular functions of immune cells including T cells, its role in CD4 + T helper cell differentiation and function is yet to be explored in detail (40)(41)(42)48). We examined the potential role of the de novo sphingolipid biosynthetic pathway in CD4 + T cell biology by using Sptlc1 conditional knockout (KO) mice, as the germline deletion of Sptlc1 is embryonic lethal (34).…”

Section: Sptlc1 Modulates Cd4 + T Helper Subset Differentiationmentioning

confidence: 99%

“…They constitute around 10 to 15% of total membrane lipids and regulate the biophysical properties of the membranes including the organization of proteins for cell recognition and signaling (33)(34)(35)(36)(37). Apart from their structural function, sphingolipids also play important roles as signaling molecules in many cell types including immune cells (33,(38)(39)(40)(41)(42)(43). Sphingolipid-mediated biological outcomes are determined by the levels of sphingolipids in the cells, which, in turn, are regulated by a balance maintained between their synthesis and catabolism (31)(32)(33).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Sphingolipid biosynthesis is essential for metabolic rewiring during T _H 17 cell differentiation

Abimannan,

Parthibane,

et al. 2024

Sci. Adv.

View full text Add to dashboard Cite

T helper 17 (T H 17) cells are implicated in autoimmune diseases, and several metabolic processes are shown to be important for their development and function. In this study, we report an essential role for sphingolipids synthesized through the de novo pathway in T H 17 cell development. Deficiency of SPTLC1 , a major subunit of serine palmitoyl transferase enzyme complex that catalyzes the first and rate-limiting step of de novo sphingolipid synthesis, impaired glycolysis in differentiating T H 17 cells by increasing intracellular reactive oxygen species (ROS) through enhancement of nicotinamide adenine dinucleotide phosphate oxidase 2 activity. Increased ROS leads to impaired activation of mammalian target of rapamycin C1 and reduced expression of hypoxia-inducible factor 1–alpha and c-Myc–induced glycolytic genes. SPTLCI deficiency protected mice from developing experimental autoimmune encephalomyelitis and experimental T cell transfer colitis. Our results thus show a critical role for de novo sphingolipid biosynthetic pathway in shaping adaptive immune responses with implications in autoimmune diseases.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Sptlc1 Modulates Cd4 + T Helper Subset Differentiationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Sphingolipid biosynthesis is essential for metabolic rewiring during T _H 17 cell differentiation

Abimannan,

Parthibane,

et al. 2024

Sci. Adv.

View full text Add to dashboard Cite

show abstract

“…STAT5 is linked to both Th1-and Th2-type effectors and is a potent inhibitor of Th17-type effectors. Induction of metabolism pathways, most notably glycolysis, glutaminolysis, OxPhos, and FAO, also varies across subsets [58,[64][65][66][67]. These disparities are often tied to the cytokines used for subset polarization (i.e., lineage-specifying cytokines) so it is likely that STATs are involved.…”

Section: Beyond Stat3 and Stat5mentioning

confidence: 99%

Transcriptional programing of T cell metabolism by STAT family transcription factors

Villarino

2023

Eur J Immunol

View full text Add to dashboard Cite

T cells adapt their metabolism to meet the energetic and biosynthetic demands imposed by changes in location, behavior, and/or differentiation state. Many of these adaptations are controlled by cytokines. Traditionally, research on the metabolic properties of cytokines has focused on downstream signaling via the PI3K‐AKT, mTOR, or ERK‐MAPK pathways but recent studies indicate that JAK‐STAT is also crucial. This review synthesizes current thinking on how JAK‐STAT signaling influences T cell metabolism, focusing on adaptations necessary for the naïve, effector, regulatory, memory, and resident‐memory states. The overarching theme is that JAK‐STAT has both direct and indirect effects. Direct regulation involves STATs localizing to and instructing expression of metabolism‐related genes. Indirect regulation involves STATs instructing genes encoding upstream or regulatory factors, including cytokine receptors and other transcription factors, as well as non‐canonical JAK‐STAT activities. Cytokines impact a vast range of metabolic processes. Here, we focus on those that are most prominent in T cells; lipid, amino acid, and nucleotide synthesis for anabolic metabolism, glycolysis, glutaminolysis, oxidative phosphorylation, and fatty acid oxidation for catabolic metabolism. Ultimately, we advocate the idea that JAK‐STAT is a key node in the complex network of signaling inputs and outputs which ensure that T cell metabolism meets lifestyle demands.

show abstract

“…It has already been shown that the activation of CD4 and CD8 T cells depends on different gangliosides in their membrane ( Nagafuku et al, 2012 ). Especially during the development of Th17 cells from Th0 cells gangliosides (GMs) and LacCer are upregulated and build a specific signature of differentiated CD4 + Th17cells ( Sen et al, 2021 ). The important role of GMs during this differentiation process is supported by the finding that a deficiency of GM3S (GM3 synthase) attenuates the differentiation of CD4 + T cells to Th17 cells ( Zhu et al, 2011 ).…”

Section: The Impact Of Sphingolipids On T Cells and Their Role In Res...mentioning

confidence: 99%

How sphingolipids affect T cells in the resolution of inflammation

2022

View full text Add to dashboard Cite

The concept of proper resolution of inflammation rather than counteracting it, gained a lot of attention in the past few years. Re-assembly of tissue and cell homeostasis as well as establishment of adaptive immunity after inflammatory processes are the key events of resolution. Neutrophiles and macrophages are well described as promotors of resolution, but the role of T cells is poorly reviewed. It is also broadly known that sphingolipids and their imbalance influence membrane fluidity and cell signalling pathways resulting in inflammation associated diseases like inflammatory bowel disease (IBD), atherosclerosis or diabetes. In this review we highlight the role of sphingolipids in T cells in the context of resolution of inflammation to create an insight into new possible therapeutical approaches.

show abstract

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

Cited by 13 publications

References 84 publications

Sphingolipid biosynthesis is essential for metabolic rewiring during T _H 17 cell differentiation

Sphingolipid biosynthesis is essential for metabolic rewiring during T _H 17 cell differentiation

Transcriptional programing of T cell metabolism by STAT family transcription factors

How sphingolipids affect T cells in the resolution of inflammation

Contact Info

Product

Resources

About

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

Cited by 13 publications

References 84 publications

Sphingolipid biosynthesis is essential for metabolic rewiring during T H 17 cell differentiation

Sphingolipid biosynthesis is essential for metabolic rewiring during T H 17 cell differentiation

Transcriptional programing of T cell metabolism by STAT family transcription factors

How sphingolipids affect T cells in the resolution of inflammation

Contact Info

Product

Resources

About

Sphingolipid biosynthesis is essential for metabolic rewiring during T _H 17 cell differentiation

Sphingolipid biosynthesis is essential for metabolic rewiring during T _H 17 cell differentiation