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

ABSTRACT: T cells undergo metabolic rewiring to meet their bioenergetic, biosynthetic and redox demands following antigen stimulation. To fulfil these needs, effector T cells must adapt to fluctuations in environmental nutrient levels at sites of infection and inflammation. Here, we show that effector T cells can utilize inosine, as an alternative substrate, to support cell growth and function in the absence of glucose in vitro. T cells metabolize inosine into hypoxanthine and phosphorylated ribose by purine nucleoside phosphorylase. We demonstrate that the ribose subunit of inosine can enter into central metabolic pathways to provide ATP and biosynthetic precursors, and that cancer cells display diverse capacities to utilize inosine as a carbon source. Moreover, the supplementation with inosine enhances the anti-tumour efficacy of immune checkpoint blockade and adoptive T-cell transfer in solid tumours that are defective in metabolizing inosine, reflecting the capability of inosine to relieve tumour-imposed metabolic restrictions on T cells.

SUBMITTER: Wang T

PROVIDER: S-EPMC7371628 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Inosine is an alternative carbon source for CD8<sup>+</sup>-T-cell function under glucose restriction.

Wang Tingting T Gnanaprakasam J N Rashida JNR Chen Xuyong X Kang Siwen S Xu Xuequn X Sun Hua H Liu Lingling L Rodgers Hayley H Miller Ethan E Cassel Teresa A TA Sun Qiushi Q Vicente-Muñoz Sara S Warmoes Marc O MO Lin Penghui P Piedra-Quintero Zayda Lizbeth ZL Guerau-de-Arellano Mireia M Cassady Kevin A KA Zheng Song Guo SG Yang Jun J Lane Andrew N AN Song Xiaotong X Fan Teresa W-M TW Wang Ruoning R

Nature metabolism 20200615 7

T cells undergo metabolic rewiring to meet their bioenergetic, biosynthetic and redox demands following antigen stimulation. To fulfil these needs, effector T cells must adapt to fluctuations in environmental nutrient levels at sites of infection and inflammation. Here, we show that effector T cells can utilize inosine, as an alternative substrate, to support cell growth and function in the absence of glucose in vitro. T cells metabolize inosine into hypoxanthine and phosphorylated ribose by pur ...[more]

PMID: 32694789

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Project description:Enzyme-IIA (EIIAGlc, Crr) of the phosphotransferase system (PTS) connects the uptake of glucose-family sugars to the cAMP-Crp regulatory cascade; phosphorylated EIIAGlc enhances cAMP-Crp activity, which then contributes to the antibiotic-mediated accumulation of reactive oxygen species (ROS) and cell death. Defects in PTS cause antibiotic and disinfectant tolerance. We report that mannitol, a carbon source whose uptake does not use EIIAGlc, reduces antibiotic-mediated killing of Escherichia coli without affecting antibiotic minimal inhibitory concentration. Thus, mannitol promotes antibiotic tolerance. The tolerance pathway was defined by the loss of ciprofloxacin lethality from the deletion of ptsI (first gene in PTS), mtlA (mannitol-specific Enzyme-II), cyaA (cAMP synthase), and crp (cAMP receptor protein) but not crr (EIIAGlc). A crp* mutant, which encodes a constitutively active Crp that bypasses the need for cAMP activation, also decreased mannitol-mediated antibiotic tolerance, as did exogenous cAMP. Thus, inhibition of antibiotic lethality by mannitol involves both PTS-mediated mannitol uptake and suppression of cAMP-Crp action, independent of EIIAGlc. Mannitol suppressed the downstream antibiotic-mediated transcription of genes involved in NADH production and cellular respiration, expression of a superoxide reporter gene (soxS), and accumulation of antibiotic-mediated ROS. Similar phenomena were observed with mannose and sorbitol, demonstrating that non-glucose PTS carbon sources can cause antibiotic tolerance by a novel path that reduces the ROS-promoting activity of cAMP-Crp. The work emphasizes that antibiotic tolerance, which contributes to disease relapse and the need for prolonged antibiotic treatment, can result from commonly consumed carbohydrates. This finding, plus mutations that interfere specifically with antibiotic lethality, makes tolerance a high probability event.IMPORTANCEBacterial tolerance constitutes a significant threat to anti-infective therapy and potentially to the use of disinfectants. Deficiency mutations that reduce glucose uptake, central carbon metabolism, and cellular respiration confer antibiotic/disinfectant tolerance by reducing the accumulation of reactive metabolites, such as reactive oxygen species. We identified novel environmental generators of tolerance by showing that non-glucose carbohydrates, such as mannitol, mannose, and sorbitol, generate tolerance to multiple antibiotic classes. Finding that these sugars inhibit a universal, stress-mediated death pathway emphasizes the potential danger of compounds that block the lethal response to severe stress. Immediate practical importance derives from mannitol being a popular food sweetener, a treatment for glaucoma, and a dehydrating agent for treating cerebral edema, including cases caused by bacterial infection: antibiotic tolerance could contra-indicate the use of mannitol and related carbohydrates during antibiotic treatment. Overall, the work shows that the presence of sugars must be considered during antimicrobial and perhaps disinfectant use.

Dataset Information

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

Publications

Inosine is an alternative carbon source for CD8<sup>+</sup>-T-cell function under glucose restriction.

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Dataset Information

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

Publications

Inosine is an alternative carbon source for CD8<sup>+</sup>-T-cell function under glucose restriction.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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