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

Nancie J. MacIver^*, Sarah R. Jacobs^,, Heather L. Wieman^,, Jessica A. Wofford^,, Jonathan L. Coloff^, and Jeffrey C. Rathmell^,^,^,1

^* Departments of Pediatrics,
Pharmacology and Cancer Biology, and
Immunology,
Sarah W. Stedman Center for Nutrition and Metabolism, Duke University Medical Center, Durham, North Carolina, USA

¹ Correspondence: Department of Pharmacology and Cancer Biology, DUMC 3813, Durham, NC 27710, USA. E-mail: jeff.rathmell{at}duke.edu

ABSTRACT

Lymphocytes require glucose uptake and metabolism for normalsurvival and function. The signals that regulate the expressionand localization of glucose transporter 1 (Glut1) to allow glucoseuptake in T cells are now beginning to be understood. RestingT cells require extracellular signals, such as cytokines, hormones,and growth factors, or low-level TCR stimulation to take upadequate glucose to maintain housekeeping functions. In theabsence of extrinsic signals, resting T cells internalize anddegrade Glut1 and cannot maintain viability. Activated T cellshave dramatically increased metabolic requirements to supportthe energy and biosynthetic needs necessary for growth, proliferation,and effector function. In particular, glucose metabolism andaerobic glycolysis fuel this demand. Therefore, activation ofT cells causes a large increase in Glut1 expression and surfacelocalization. If glucose uptake is limited, glycolytic fluxdecreases to a level that no longer sustains viability, andproapoptotic Bcl-2 family members become activated, promotingcell death. However, excessive glucose uptake can promote hyperactiveimmune responses and possible immune pathology. Tight regulationof glucose uptake is required to maintain immune homeostasis,and understanding of these metabolic pathways may lead to therapeuticstrategies to target some forms of cancer or autoimmunity.

Key Words: aerobic glycolysis • Glut1 • Akt • IL-7 • CD28