Glucose Uptake Is Limiting in T Cell Activation and Requires CD28-Mediated Akt-Dependent and Independent Pathways

Jacobs, Sarah R.; Herman, Catherine E.; MacIver, Nancie J.; Wofford, Jessica A.; Wieman, Heather L.; Hammen, Jeremy J.; Rathmell, Jeffrey C.

doi:10.4049/jimmunol.180.7.4476

Cited by 716 publications

(811 citation statements)

References 47 publications

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“…Because facilitated metabolism is coupled to consumption of large amounts of intracellular materials such as amino acids and glucose, T cells must boost the rate of uptake of those nutrients by setting up special devices such as effective organic solute transporters. Supporting this notion, the glucose transporter 1 is upregulated upon activation of T cells (4)(5)(6). T cells also must enhance amino acid uptake rate to support increased protein synthesis accompanied by cytokine production and cell proliferation during activation.…”

mentioning

confidence: 81%

LAT1 Is a Critical Transporter of Essential Amino Acids for Immune Reactions in Activated Human T Cells

Hayashi

Jutabha

Endou³

et al. 2013

The Journal of Immunology

143

117

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Activation of T cells accompanies remarkable enhancement of metabolism. Sufficient and continuous nutrient supply is therefore important to support immune reaction in T cells. However, the mechanism of the promotion of nutrient incorporation in activated T cells has not been elucidated. In this study, we show that L-type amino acid transporter 1 (LAT1) is a major transporter for essential amino acids into activated human T cells. CD3/CD28 stimulation in primary human T cells triggered dramatic induction of LAT1 expression mediated by NF-κB and AP-1. Functional disturbance of LAT1 by a specific inhibitor and by small interfering RNA in human T cells suppressed essential amino acid uptake and induced a stress response mediated by DNA damage–inducible transcript 3 to attenuate cytokine production via inhibition of NF-κB and NFAT activities. These results uncover the previously unknown mechanism by which T cells accelerate essential amino acid uptake upon activation and adapt to essential amino acid starvation. Our results also raise the possibility for application of an LAT1 inhibitor as a new drug for therapy of disease caused by exaggerated immune response.

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mentioning

confidence: 81%

LAT1 Is a Critical Transporter of Essential Amino Acids for Immune Reactions in Activated Human T Cells

Hayashi

Jutabha

Endou³

et al. 2013

The Journal of Immunology

143

117

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“…In response to activation, T cells exhibit a remarkable metabolic shift from fatty acid oxidation to glycolysis (50)(51)(52). Thus, increased sugar metabolism may lead to higher levels of UDP-GlcNAc, which would promote OGT activity.…”

Section: T Cell Activation Leads To Regulation Of Ogt Localization Anmentioning

confidence: 99%

Global Analysis of O-GlcNAc Glycoproteins in Activated Human T Cells

Lund

Elias

Davis

2016

The Journal of Immunology

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T cell activation in response to Ag is largely regulated by protein posttranslational modifications. Although phosphorylation has been extensively characterized in T cells, much less is known about the glycosylation of serine/threonine residues by O-linked N-acetylglucosamine (O-GlcNAc). Given that O-GlcNAc appears to regulate cell signaling pathways and protein activity similarly to phosphorylation, we performed a comprehensive analysis of O-GlcNAc during T cell activation to address the functional importance of this modification and to identify the modified proteins. Activation of T cells through the TCR resulted in a global elevation of O-GlcNAc levels and in the absence of O-GlcNAc, IL-2 production and proliferation were compromised. T cell activation also led to changes in the relative expression of O-GlcNAc transferase (OGT) isoforms and accumulation of OGT at the immunological synapse of murine T cells. Using a glycoproteomics approach, we identified >200 O-GlcNAc proteins in human T cells. Many of the identified proteins had a functional relationship to RNA metabolism, and consistent with a connection between O-GlcNAc and RNA, inhibition of OGT impaired nascent RNA synthesis upon T cell activation. Overall, our studies provide a global analysis of O-GlcNAc dynamics during T cell activation and the first characterization, to our knowledge, of the O-GlcNAc glycoproteome in human T cells.

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“…C57BL/6 mice were obtained from Jackson Laboratories, and Glut1 transgenic and ERRα −/− mice were previously described (2,24). Mice were housed and cared for at Duke University under an Institutional Animal Care and Use Committee approved protocol.…”

Section: Methodsmentioning

confidence: 99%

“…These processes require energy expenditure and biosynthesis (2,3) and T-cell stimulation triggers a rapid increase in cellular metabolism to support activation and differentiation pathways (4,5). We have shown that specific metabolic demands differ between CD4 + T-cell subsets, as Teff cells (Th1, Th2, and Th17) are dependent upon glycolysis, while Tregs use and require lipid oxidation (6).…”

mentioning

confidence: 99%

Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation

Michalek¹,

Gerriets²,

Nichols³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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197

189

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Stimulation of resting CD4 + T lymphocytes leads to rapid proliferation and differentiation into effector (Teff) or inducible regulatory (Treg) subsets with specific functions to promote or suppress immunity. Importantly, Teff and Treg use distinct metabolic programs to support subset specification, survival, and function. Here, we describe that the orphan nuclear receptor estrogen-related receptor-α (ERRα) regulates metabolic pathways critical for Teff. Resting CD4 + T cells expressed low levels of ERRα protein that increased on activation. ERRα deficiency reduced activated T-cell numbers in vivo and cytokine production in vitro but did not seem to modulate immunity through inhibition of activating signals or viability. Rather, ERRα broadly affected metabolic gene expression and glucose metabolism essential for Teff. In particular, up-regulation of Glut1 protein, glucose uptake, and mitochondrial processes were suppressed in activated ERRα −/− T cells and T cells treated with two chemically independent ERRα inhibitors or by shRNAi. Acute ERRα inhibition also blocked T-cell growth and proliferation. This defect appeared as a result of inadequate glucose metabolism, because provision of lipids, but not increased glucose uptake or pyruvate, rescued ATP levels and cell division. Additionally, we have shown that Treg requires lipid oxidation, whereas Teff uses glucose metabolism, and lipid addition selectively restored Tregbut not Teff-generation after acute ERRα inhibition. Furthermore, in vivo inhibition of ERRα reduced T-cell proliferation and Teff generation in both immunization and experimental autoimmune encephalomyelitis models. Thus, ERRα is a selective transcriptional regulator of Teff metabolism that may provide a metabolic means to modulate immunity. glycolysis | fatty acid | oxidative metabolism | mammalian target of rapamycin | AMPK

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Glucose Uptake Is Limiting in T Cell Activation and Requires CD28-Mediated Akt-Dependent and Independent Pathways

Cited by 716 publications

References 47 publications

LAT1 Is a Critical Transporter of Essential Amino Acids for Immune Reactions in Activated Human T Cells

LAT1 Is a Critical Transporter of Essential Amino Acids for Immune Reactions in Activated Human T Cells

Global Analysis of O-GlcNAc Glycoproteins in Activated Human T Cells

Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation

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