Non-oxidative pentose phosphate pathway controls regulatory T cell function

We are very pleased to share the autoimmune disease study published in Nature Metabolism Journal. The authors of "Non-oxidative pentose phosphate pathway controls regulatory T cell function by integrating metabolism and epigenetics" utilized our proprietary energy targeted metabolism detection and reported 50+ energy metabolites. The aim of this study was to explore how the non-oxidized pentose phosphate pathway (PPP) regulates T_reg function to prevent autoimmunity.

Regulatory T cells (T_reg), as a master suppressor of the immune system, limit immune-derived inflammation by preventing effector T cells from exhibiting excessive activation, proliferation or cytokine production. When T_reg cells switch from quiescence to rapid proliferation upon antigen stimulation diseases, metabolic conversion is required to generate energy and macromolecules from nutrients to match functional demands. T_reg cells have been reported to rely more on fatty acid β-oxidation and oxidative phosphorylation (OXPHOS) to support their function. However, the difficulties of targeting the X-chromosome-encoded transcription factor FOXP3 or these canonical metabolic pathways emphasize the need to explore new mechanisms to control T_reg function.

Being a fundamental component of cellular metabolism, the non-oxidative pentose phosphate pathway (PPP) not only bridges glycolytic intermediates and ribose-5-phosphate (R5P), but also regulates glucose-derived carbon feeding into the tricarboxylic acid cycle (TCA cycle) in metabolic tissues. The non-oxidative PPP originating from ribulose-5-phosphate, a terminal metabolite in oxidative PPP, consists of several reversible reactions. Transketolase (TKT) stands out among the non-oxidative PPP enzymes by catalysing two reversible reactions, including the conversion of Xu5P and R5P to glyceraldehyde-3-phosphate (G3P) and sedoheptulose-7-phosphate (S7P) as well as the conversion of Xu5P and erythrose-4-phosphate to G3P and fructose-6-phosphate (F6P). By constructing a T_reg-specific TKT-deficient mouse model, the authors found that the TKT knockout blocked the immunosuppressive function of T_reg cells, leading to severe autoimmune diseases, which reveals a pivotal role of non-oxidized PPP in maintaining T_reg function.

Comparing levels of amino acid metabolism in T_reg cells of WT and cKO mice aged 2 to 3 weeks using LC-MS/MS, the author discovered that non-oxidative PPP balances fuel catabolism in T_reg cells. TKT deficiency significantly reduced amino acid levels in T_reg cells. The [¹³C₆] isoleucine tracing assay indicated that more amino acids entered the TCA cycle in cKO T_reg cells. The absence of TKT in T_reg cells caused metabolic remodeling, such as activation of amino acid catabolism, activation of fatty acid metabolism, and reduction of glucose catabolism.

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TCA cycle intermediates regulate epigenetic homeostasis in cancer and immune cells. Performing targeted cancer metabolomics towards central metabolism, especially the TCA cycle in WT and cKO Treg cells from 2- to 3-week-old mice with mild inflammation, the authors found that the non-oxidative PPP plays a critical role in dividing carbon flows between glycolysis and de novo nucleotide biosynthesis. Limited lactate production and increased nucleotide biosynthesis could be observed in TKT-deficient T_reg cells. Taken together, reduced glycolysis and enhanced oxidative stress induced by TKT deficiency triggers excessive fatty acid and amino acid catabolism, resulting in uncontrolled oxidative phosphorylation and impaired mitochondrial fitness. Reduced α-KG levels as a result of reductive TCA cycle activity leads to DNA hypermethylation, thereby limiting functional gene expression and suppressive activity of TKT-deficient T_reg cells.

In conclusion, the non-oxidative PPP serves as a metabolic gatekeeper to balance T_reg catabolism and transcriptome and epigenetic programmes, which specifically orchestrates T_reg function and activates T_reg differentiation.

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