CD4+ T-cell differentiation and function: Unifying glycolysis, fatty acid oxidation, polyamines NAD mitochondria

Almeida, Luís; Dhillon-LaBrooy, Ayesha; Carriche, Guilhermina M.; Berod, Luciana; Sparwasser, Tim

doi:10.1016/j.jaci.2021.03.033

Cited by 62 publications

(35 citation statements)

References 185 publications

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“…has been shown to promote IL-9 expression in murine T H cells by activating HIF-1α, which has a direct binding site on the IL9 promoter (18). Therefore, our study further supports the notion that distinct metabolic pathways can have a selective effect on the T H cell effector function and, in principle, demonstrates that these immunometabolic links could be leveraged for targeted manipulation of immune function (29).…”

Section: Discussionsupporting

confidence: 82%

PPAR-γ regulates the effector function of human T_H9 cells by promoting glycolysis

Bertschi

Steck

Luther

et al. 2022

Preprint

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T helper 9 cells (TH9) are key drivers of allergic tissue inflammation. They are characterized by the expression of type 2 cytokines, such as IL-9 and IL-13, and the peroxisome proliferator-activated receptor gamma (PPAR-γ) transcription factor. However, the functional role of PPAR-γ in human TH9 cells remains unknown. Here, we demonstrate that PPAR-γ drives activation-induced glycolysis, which, in turn, specifically promotes the expression of IL-9, but not IL-13, in an mTORC1-dependent manner. In vitro and ex vivo experiments on skin samples of allergic contact dermatitis showed that the PPAR-γ-mTORC1-IL-9 pathway was active in TH9 cells in human skin inflammation. Additionally, we found that tissue glucose levels were dynamically regulated in acute allergic skin inflammation, suggesting that in situ glucose availability is linked to distinct immunological signals in vivo. Furthermore, paracrine IL-9 induced the lactate transporter MCT1 in IL-9R+ TH cells, where it increased aerobic glycolysis and proliferative capacity. Taken together, our findings delineate a hitherto unknown relationship between PPAR-γ-dependent glucose metabolism and the pathogenic effector function of human TH9 cells.

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Section: Discussionsupporting

confidence: 82%

PPAR-γ regulates the effector function of human T_H9 cells by promoting glycolysis

Bertschi

Steck

Luther

et al. 2022

Preprint

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“…It is not known whether this reflects selectivity by fatty acid transporters and/or competition between n-6 and n-3 EFA. Newly assimilated EFA may then be partitioned towards beta-oxidation ( 60 ), which can contribute 50%–90% of ATP synthesis in leukocytes ( 61 ), and membrane synthesis to support programmed changes in T-cell membrane fatty acid composition that are associated with blastogenesis ( 19 – 21 , 23 , 24 ), synthesis of LCPUFA, or enzymatic oxidation to form oxylipins. The present findings show that partitioning between oxylipin synthesis and conversion to LCPUFA is a branch point in EFA metabolism, although differential distribution between the remaining fates cannot be deduced from these data.…”

Section: Discussionmentioning

confidence: 99%

The Partitioning of Newly Assimilated Linoleic and α-Linolenic Acids Between Synthesis of Longer-Chain Polyunsaturated Fatty Acids and Hydroxyoctadecaenoic Acids Is a Putative Branch Point in T-Cell Essential Fatty Acid Metabolism

et al. 2021

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Longer-chain polyunsaturated fatty acids (LCPUFAs) ≥20 carbons long are required for leukocyte function. These can be obtained from the diet, but there is some evidence that leukocytes can convert essential fatty acids (EFAs) into LCPUFAs. We used stable isotope tracers to investigate LCPUFA biosynthesis and the effect of different EFA substrate ratios in human T lymphocytes. CD3+ T cells were incubated for up to 48 h with or without concanavalin A in media containing a 18:2n-6:18:3n-3 (EFA) ratio of either 5:1 or 8:1 and [13C]18:3n-3 plus [d5]18:2n-6. Mitogen stimulation increased the amounts of 16:1n-7, 18:1n-9, 18:2n-6, 20:3n-6, 20:4n-6, 18:3n-3, and 20:5n-3 in T cells. Expression of the activation marker CD69 preceded increased FADS2 and FADS1 mRNA expression and increased amounts of [d5]20:2n-6 and [13C]20:3n-3 at 48 h. In addition, 22-carbon n-6 or n-3 LCPUFA synthesis was not detected, consistent with the absence of ELOVL2 expression. An EFA ratio of 8:1 reduced 18:3n-3 conversion and enhanced 20:2n-6 synthesis compared to a 5:1 ratio. Here, [d5]9- and [d5]-13-hydroxyoctadecadienoic (HODE) and [13C]9- and [13C]13-hydroxyoctadecatrienoic acids (HOTrE) were the major labelled oxylipins in culture supernatants; labelled oxylipins ≥20 carbons were not detected. An EFA ratio of 8:1 suppressed 9- and 13-HOTrE synthesis, but there was no significant effect on 9- and 13-HODE synthesis. These findings suggest that partitioning of newly assimilated EFA between LCPUFA synthesis and hydroxyoctadecaenoic acid may be a metabolic branch point in T-cell EFA metabolism that has implications for understanding the effects of dietary fats on T lymphocyte function.

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“…Accordingly, we presume that timing and personalized diet should be taken into account when applying glucose restriction to supplement ICI treatment. Likewise, the lipid and amino acid metabolisms function differently at different stages of differentiation and activation of immune cells, thus the need for nutrients varies [ 120 , 150 - 152 ] . Therefore, it is critical to understand the metabolic network and landscape in TME in KRAS-driven NSCLC and how they affect the behavior of tumor cells and the function of stromal cells.…”

Section: Prospective Strategies For Overcoming Resistance To Icismentioning

confidence: 99%

Resistance to immune checkpoint inhibitors in KRAS-mutant non-small cell lung cancer

Li¹,

Hu²,

Peng³

et al. 2022

CDR

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Non-small cell lung cancer (NSCLC) patients with Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation are associated with significant clinical heterogeneity and a poor prognosis to standard NSCLC therapies such as surgical resection, radiotherapy, chemotherapies, and targeted medicines. However, the application of immune checkpoints inhibitors (ICIs) has dramatically altered the therapeutic pattern of NSCLC management. Clinical studies have indicated that some KRAS-mutant NSCLC patients could benefit from ICIs; however, the responses in some patients are still poor. This review intends to elucidate the mechanisms of resistance to immunotherapy in KRAS-driven NSCLC and highlight the TME functions altered by immunoinhibitors, immunostimulators, and cancer metabolism. These metabolic pathways could potentially be promising approaches to overcome immunotherapy resistance.

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CD4+ T-cell differentiation and function: Unifying glycolysis, fatty acid oxidation, polyamines NAD mitochondria

Cited by 62 publications

References 185 publications

PPAR-γ regulates the effector function of human T_H9 cells by promoting glycolysis

PPAR-γ regulates the effector function of human T_H9 cells by promoting glycolysis

The Partitioning of Newly Assimilated Linoleic and α-Linolenic Acids Between Synthesis of Longer-Chain Polyunsaturated Fatty Acids and Hydroxyoctadecaenoic Acids Is a Putative Branch Point in T-Cell Essential Fatty Acid Metabolism

Resistance to immune checkpoint inhibitors in KRAS-mutant non-small cell lung cancer

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CD4+ T-cell differentiation and function: Unifying glycolysis, fatty acid oxidation, polyamines NAD mitochondria

Cited by 62 publications

References 185 publications

PPAR-γ regulates the effector function of human TH9 cells by promoting glycolysis

PPAR-γ regulates the effector function of human TH9 cells by promoting glycolysis

The Partitioning of Newly Assimilated Linoleic and α-Linolenic Acids Between Synthesis of Longer-Chain Polyunsaturated Fatty Acids and Hydroxyoctadecaenoic Acids Is a Putative Branch Point in T-Cell Essential Fatty Acid Metabolism

Resistance to immune checkpoint inhibitors in KRAS-mutant non-small cell lung cancer

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PPAR-γ regulates the effector function of human T_H9 cells by promoting glycolysis

PPAR-γ regulates the effector function of human T_H9 cells by promoting glycolysis