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Review
. 2008 Oct;84(4):949-57.
doi: 10.1189/jlb.0108024. Epub 2008 Jun 24.

Glucose metabolism in lymphocytes is a regulated process with significant effects on immune cell function and survival

Nancie J Maciver  1 , Sarah R Jacobs, Heather L Wieman, Jessica A Wofford, Jonathan L Coloff, Jeffrey C Rathmell
Affiliations
Review

Glucose metabolism in lymphocytes is a regulated process with significant effects on immune cell function and survival

Nancie J Maciver et al. J Leukoc Biol. 2008 Oct.

Abstract

Lymphocytes require glucose uptake and metabolism for normal survival and function. The signals that regulate the expression and localization of glucose transporter 1 (Glut1) to allow glucose uptake in T cells are now beginning to be understood. Resting T cells require extracellular signals, such as cytokines, hormones, and growth factors, or low-level TCR stimulation to take up adequate glucose to maintain housekeeping functions. In the absence of extrinsic signals, resting T cells internalize and degrade Glut1 and cannot maintain viability. Activated T cells have dramatically increased metabolic requirements to support the energy and biosynthetic needs necessary for growth, proliferation, and effector function. In particular, glucose metabolism and aerobic glycolysis fuel this demand. Therefore, activation of T cells causes a large increase in Glut1 expression and surface localization. If glucose uptake is limited, glycolytic flux decreases to a level that no longer sustains viability, and proapoptotic Bcl-2 family members become activated, promoting cell death. However, excessive glucose uptake can promote hyperactive immune responses and possible immune pathology. Tight regulation of glucose uptake is required to maintain immune homeostasis, and understanding of these metabolic pathways may lead to therapeutic strategies to target some forms of cancer or autoimmunity.

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Figures

Fig. 1.
Fig. 1.
T cells require glucose for proliferation and survival. T cells were cultured in limited glucose concentration on plates coated with 5 μg/ml anti-CD3 and 5 μg/ml anti-CD28 for 48 h. (A) Cell proliferation was measured by CFSE staining, and the percentage of cells that divided at least twice was quantified. (B) Cell survival was measured flow cytometrically by propidium iodide exclusion.
Fig. 2.
Fig. 2.
Activation of Akt leads to increased glucose uptake. Growth factor or cytokine binding to its receptor on the T cell causes activation of PI-3K, thus converting phosphatidylinositol (PI) to PI 3,4,5 trisphosphate (PIP3), thereby recruiting Akt to the cell surface, where it becomes activated and in turn, up-regulates surface Glut1 expression, glucose uptake, and glycolysis. PTEN, Phosphatase and tensin homologue.
Fig. 3.
Fig. 3.
Activated T cells take up more glucose. T cells were isolated from wild-type mice and cultured for 24 h without treatment (neglect) or with 1 or 5 μg/ml anti-CD3, with or without 5 μg/ml anti-CD28. Glucose uptake of live cells was determined.
Fig. 4.
Fig. 4.
CD28 costimulation influences Glut1 trafficking. High levels of TCR signal alone are sufficient to increase Glut1 protein levels without costimulation. Low levels of TCR signal require costimulation to increase Glut1 protein levels. CD28 costimulation promotes Glut1 trafficking.
Fig. 5.
Fig. 5.
AMPK activation in T cells. (A) AMPK is activated in T cells in one of two ways: by energy deprivation via LKB1 kinase or by TCR activation via CAMKK2. AMPK activation causes an increase in ATP-generating metabolic processes while decreasing ATP-consuming processes. (B) Within minutes of TCR signaling, AMPK activity is up-regulated, and ATP is most likely generated via oxidative phosphorylation. Within a few hours, Glut1 can be trafficked to the cell surface, and new Glut1 protein is expressed such that glucose uptake stimulates aerobic glycolysis.
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