Acetate Promotes T Cell Effector Function during Glucose Restriction

Qiu, Jing; Villa, Matteo; Sanin, David E.; Buck, Michael D.; O’Sullivan, David; Ching, Reagan W.; Matsushita, Mai; Grzes, Katarzyna M.; Winkler, Frances; Chang, Chih‐Hao; Curtis, Jonathan D.; Kyle, Ryan; Bakker, Nikki van Teijlingen; Corrado, Mauro; Haessler, Fabian; Alfei, Francesca; Edwards-Hicks, Joy; Maggi, Leonard B.; Zehn, Dietmar; Egawa, Takeshi; Bengsch, Bertram; Geltink, Ramon I. Klein; Jenuwein, Thomas; Pearce, Edward J.; Pearce, Erika L.

doi:10.1016/j.celrep.2019.04.022

Cited by 217 publications

(168 citation statements)

References 65 publications

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“…T cells may utilize inosine and adenosine accumulated in the TME as an important carbon and energy source. In addition, T cells are capable of utilizing acetate as alternative substrate to support bioenergetic activity and effector function in the TME 55 .…”

Section: Discussionmentioning

confidence: 99%

Inosine is an alternative carbon source for CD8+-T-cell function under glucose restriction

et al. 2020

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Section: Discussionmentioning

confidence: 99%

Inosine is an alternative carbon source for CD8+-T-cell function under glucose restriction

et al. 2020

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“…Importantly, ACSS2 is upregulated upon treatment interruption in ART-suppressed individuals [126]. ACSS2 is an essential enzyme in controlling lipid or fatty acid metabolism [127] and has been shown to play important roles in T cell function [128]. HIV-1 expression has been shown to alter lipid metabolism in CD4 + T cells [129].…”

Section: Post-translational Modifications Of Histonesmentioning

confidence: 99%

Key Players in HIV-1 Transcriptional Regulation: Targets for a Functional Cure

Mori¹,

Valente²

2020

Viruses

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HIV-1 establishes a life-long infection when proviral DNA integrates into the host genome. The provirus can then either actively transcribe RNA or enter a latent state, without viral production. The switch between these two states is governed in great part by the viral protein, Tat, which promotes RNA transcript elongation. Latency is also influenced by the availability of host transcription factors, integration site, and the surrounding chromatin environment. The latent reservoir is established in the first few days of infection and serves as the source of viral rebound upon treatment interruption. Despite effective suppression of HIV-1 replication by antiretroviral therapy (ART), to below the detection limit, ART is ineffective at reducing the latent reservoir size. Elimination of this reservoir has become a major goal of the HIV-1 cure field. However, aside from the ideal total HIV-1 eradication from the host genome, an HIV-1 remission or functional cure is probably more realistic. The “block-and-lock” approach aims at the transcriptional silencing of the viral reservoir, to render suppressed HIV-1 promoters extremely difficult to reactivate from latency. There are unfortunately no clinically available HIV-1 specific transcriptional inhibitors. Understanding the mechanisms that regulate latency is expected to provide novel targets to be explored in cure approaches.

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“…However, much less is known about how energy metabolism and the metabolic microenvironment affects immune responses [ 13 ]. Observations in immunometabolism have reported that peripheral immune cells can adapt to fluctuating environmental challenges by metabolising alternative nutrients other than glucose, such as acetate [ 14 ], amino acids [ 15 ], or fatty acids [ 13 , 16 ]. In microglia, this phenomenon of the so-called metabolic flexibility and the utilisation of alternative substrates other that glucose is still poorly understood.…”

Section: Introductionmentioning

confidence: 99%

β-Hydroxybutyrate Oxidation Promotes the Accumulation of Immunometabolites in Activated Microglia Cells

et al. 2020

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Metabolic regulation of immune cells has arisen as a critical set of processes required for appropriate response to immunological signals. While our knowledge in this area has rapidly expanded in leukocytes, much less is known about the metabolic regulation of brain-resident microglia. In particular, the role of alternative nutrients to glucose remains poorly understood. Here, we use stable-isotope (13C) tracing strategies and metabolomics to characterize the oxidative metabolism of β-hydroxybutyrate (BHB) in human (HMC3) and murine (BV2) microglia cells and the interplay with glucose in resting and LPS-activated BV2 cells. We found that BHB is imported and oxidised in the TCA cycle in both cell lines with a subsequent increase in the cytosolic NADH:NAD+ ratio. In BV2 cells, stimulation with LPS upregulated the glycolytic flux, increased the cytosolic NADH:NAD+ ratio and promoted the accumulation of the glycolytic intermediate dihydroxyacetone phosphate (DHAP). The addition of BHB enhanced LPS-induced accumulation of DHAP and promoted glucose-derived lactate export. BHB also synergistically increased LPS-induced accumulation of succinate and other key immunometabolites, such as α-ketoglutarate and fumarate generated by the TCA cycle. Finally, BHB upregulated the expression of a key pro-inflammatory (M1 polarisation) marker gene, NOS2, in BV2 cells activated with LPS. In conclusion, we identify BHB as a potentially immunomodulatory metabolic substrate for microglia that promotes metabolic reprogramming during pro-inflammatory response.

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Acetate Promotes T Cell Effector Function during Glucose Restriction

Abstract: Highlights d Acetate restores IFN-g in TILs and T cells under prolonged glucose-restriction d Acetate promotes histone acetylation and chromatin accessibility in T cells d ACSS expression contributes to optimal effector T cell function during cancer

Cited by 217 publications

References 65 publications

Inosine is an alternative carbon source for CD8+-T-cell function under glucose restriction

Inosine is an alternative carbon source for CD8+-T-cell function under glucose restriction

Key Players in HIV-1 Transcriptional Regulation: Targets for a Functional Cure

β-Hydroxybutyrate Oxidation Promotes the Accumulation of Immunometabolites in Activated Microglia Cells

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