Dataset Information

A metabolism-epigenome axis controls early events in CD4+ T cell activation

ABSTRACT: Upon antigen-specific T Cell Receptor (TCR) engagement, human CD4+ T cells proliferate and differentiate, a process associated with rapid transcriptional changes and metabolic reprogramming utilizing aerobic glycolysis together with maintenance of oxidative phosphorylation1,2. However, the role of glycolytic-reprogramming during T-cell activation remains largely unclear3,4,5. Here, we show that maintenance of cytosolic pyruvate production is an essential requirement for remodeling of the CD4+ T cell epigenome after TCR-engagement. Furthermore, we provide evidence that the local inflammatory environment sustains metabolic reprogramming of CD4+ T-cells and impacts histone modification in a pyruvate-dependent manner. Mechanistically, we demonstrate that rapid and sustained generation of cytosolic, but not mitochondrial, pyruvate is an essential step for acetyl-coA production and subsequent H3K27ac epigenome remodeling. TCR-activation was found to induce nuclear import of pyruvate dehydrogenase (PDH) and its association with both the p300 acetyltransferase and histone H3K27ac. Disrupting PDH nuclear import impacted expression of activation-induced genes. These results reveal a direct connection between CD4+ T cell metabolic reprogramming and transcriptional regulation, with the generation of cytosolic pyruvate being an essential step in T cell activation. These data support tight integration of metabolic enzymes and histone modifying enzymes, allowing metabolic reprogramming to fuel CD4+ T cell activation.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): T Cell

SUBMITTER: Harmjan Vos

LAB HEAD: Paul J Coffer

PROVIDER: PXD018132 | Pride | 2023-10-27

REPOSITORIES: Pride

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			Action	DRS
	20190201_F1_RS_EMG_0226_A1_2.raw	Raw
	20190201_F1_RS_EMG_0226_A2_2.raw	Raw
	20190201_F1_RS_EMG_0226_AP2_2.raw	Raw
	20190201_F1_RS_EMG_0226_AP3_2.raw	Raw
	20190201_F1_RS_EMG_0226_R1_2.raw	Raw

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Publications

Pyruvate metabolism controls chromatin remodeling during CD4<sup>+</sup> T cell activation.

Mocholi Enric E Russo Laura L Gopal Keshav K Ramstead Andrew G AG Hochrein Sophia M SM Vos Harmjan R HR Geeven Geert G Adegoke Adeolu O AO Hoekstra Anna A van Es Robert M RM Pittol Jose Ramos JR Vastert Sebastian S Rutter Jared J Radstake Timothy T van Loosdregt Jorg J Berkers Celia C Mokry Michal M Anderson Colin C CC O'Connell Ryan M RM Vaeth Martin M Ussher John J Burgering Boudewijn M T BMT Coffer Paul J PJ

Cell reports 20230601 6

Upon antigen-specific T cell receptor (TCR) engagement, human CD4<sup>+</sup> T cells proliferate and differentiate, a process associated with rapid transcriptional changes and metabolic reprogramming. Here, we show that the generation of extramitochondrial pyruvate is an important step for acetyl-CoA production and subsequent H3K27ac-mediated remodeling of histone acetylation. Histone modification, transcriptomic, and carbon tracing analyses of pyruvate dehydrogenase (PDH)-deficient T cells sho ...[more]

PMID: 37267106

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Project description:T cell activation is known to require a metabolic shift towards glycolysis, triggered by TCR-engagement . To substantiate the role of glycolysis in transcriptional reprogramming during antigen-driven T cell activation, we utilized a well-established ex-vivo model to recapitulate the process of antigen stimulation without the requirement for additional antigen-presenting cells . We initially explored and validated the conditions for both metabolic and epigenetic reprogramming. Antigen-mediated CD4+ T cells activation initiates context-specific gene-expression programs that drive effector functions and cell fates through changes in the epigenetic landscape . To evaluate global changes in histone modifications, we isolated CD4+ T cells from peripheral blood (PB) of healthy control (HC) human donors and either maintained them in resting conditions or stimulated with anti-CD3/CD28 for 24h. Rapid changes in the CD4+ epigenome and transcriptome were observed within 24h as measured by RNA-sequencing (RNA-seq) and H3K27ac chromatin immunoprecipitation followed by DNA-sequencing (ChIP-seq).To explore the requirement for metabolic reprogramming in regulating transcriptional responses after initial TCR engagement, CD4+ T cells from PB of healthy donors were isolated and activated in either the presence or absence of oligomycin (inhibitor of ATP synthase blocking the production of ATP by OXPHOS), 2-deoxyglucose (2DG; competitively inhibiting production of glucose-6-phosphate from glucose), or replacement of glucose with galactose. Galactose is metabolized through glycolysis, utilizing the Leloir pathway which is energy neutral, forcing cells to use all the pyruvate production to sustain the TCA cycle for OXPHOS and ATP synthesis at the expense of lactate production. Employing ChIP-seq and RNA-seq, inhibition of OXPHOS-mediated ATP production by oligomycin had only a limited effect on H3K27-acetylation or activation-induced transcription during the first 24h of activation. In contrast, inhibition of glycolysis by 2DG treatment compromised both H3K27-acetylation and transcriptional changes. However, under conditions of galactose-metabolism where lactate production is abrogated, activated CD4+ T cells were still able to globally remodel H3K27 acetylation and reprogram the transcriptome.