H3K9bhb identification of CD8+Tm cells
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Q Exactive
ORGANISM(S): Mus Musculus (mouse)
TISSUE(S): Spleen, T Cell
SUBMITTER: 
Huafeng Zhang
LAB HEAD: Bo Huang
PROVIDER: PXD016044 | Pride | 2019-11-14
REPOSITORIES: Pride
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Project description:Elucidation of metabolic flux and switch is fundamental for understanding of CD8+ memory T (Tm) cell development. Glycogen, an intracellular carbon reservoir, has long been functionally considered as the use of energy metabolism. However, our recent study indicated that glycogen metabolism, directed by a cytosolic phosphoenolpyruvate carboxykinase (Pck1), controls the formation and maintenance of CD8+ Tm cells through regulating the redox homeostasis1. This unusual metabolic program raises the question of how Pck1 is upregulated in CD8+ Tm cells. Here, we show that mitochondrial acetyl-CoA is shunted to ketogenesis, which indirectly regulates Pck1 expression. Mechanistically, ketogenesis-derived β-hydroxybutyrate (BHB) is stocked in CD8+ Tm cells, which epigenetically modifies H3K9 of FoxO1 and PGC-1α with β-hydroxybutyrylation so to upregulate these genes expression. As a result, FoxO1 and PGC-1α cooperatively upregulates Pck1 expression, thus directing the carbon flow along the gluconeogenic pathway to glycogen and the pentose phosphate pathway. These results unveil that the ketogenesis acts as an unusual metabolic pathway in CD8+ Tm cells, linking epigenetic modification required for memory development.
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Project description:Memory T cells (TM) play a prominent role in protection and auto-immunity due to their ability to mount a more effective response than naïve T cells (TN). However, the molecular mechanisms underlying enhanced functionality of TM are not well defined, particularly in human TM. We examined the global gene expression profiles of human CD8+ TN and TM before and after stimulation. There were 1,284, 1,373 and 1,629 differentially expressed genes between TN and TM at 0 hr, 4 hr and 24 hr after stimulation, respectively, with more genes expressed to higher levels in TM. Genes rapidly up-regulated in TN cells were largely involved in nitrogen, nucleoside and amino acid metabolisms. In contrast, those in CD8+ TM were significantly enriched for immune-response-associated processes, including cytokine production, lymphocyte activation and chemotaxis. Multiple cytokines were rapidly up-regulated in TM cells, including effector cytokines known to be produced by CD8+ T cells and important for their functions, as well as regulatory cytokines, both pro- and anti-inflammatory, that are not typically produced by CD8+ T cells. These results provide new insights into molecular mechanisms that contribute to the enhanced functionality of human CD8+ TM and their prominent role in protection and auto-immunity. Naïve and memory phenotype CD8 T cells were purified by FACS from healthy individuals and cultured in vitro with the stimulation of anti-CD3/CD28 mAbs for 0 hr, 4 hr and 24 hr. Total RNA was purified from un-stimulated and stimulated naive and memory CD8 T cells and hybridized to individual single-color arrays.The purification and stimulation protocol was performed two independent times.
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