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Anergic T Cells Are Metabolically Anergic¹

The Sidney-Kimmel Cancer Research Center, The Johns Hopkins School of Medicine, Baltimore, MD 21231

Full T cell activation requires TCR engagement (signal 1) in the context of costimulation (signal 2). Costimulation is required for maximal expression of effector cytokines and prevention of T cell anergy. It has become increasingly clear that another major function of costimulation is to up-regulate the metabolic machinery necessary for T cell function. In this report we demonstrate that anergic T cells are metabolically anergic, in that upon full stimulation (signals 1 plus 2) they fail to up-regulate the machinery necessary to support increased metabolism. These findings suggest that one mechanism responsible for the maintenance of T cell anergy is failure to up-regulate the metabolic machinery. Furthermore, we demonstrate that by blocking leucine, glucose, and energy metabolism, T cell activation is mitigated. Additionally, inhibition of these metabolic pathways during T cell activation leads to anergy in Th1-differentiated cells. Overall, our findings extend the role of T cell metabolism in regulating T cell function.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by National Institutes of Health Grants R01CA098109 and R01CA14227 and by an Ajinomoto Pilot Project grant.

² Y.Z., G.M.D., and C.F.M. contributed equally to this manuscript.

³ Address correspondence and reprint requests to Dr. Jonathan D. Powell, The Sidney-Kimmel Cancer Research Center, The Johns Hopkins School of Medicine, 1650 Orleans Street, Baltimore, MD 21231. E-mail address: poweljo{at}jhmi.edu

⁴ Abbreviations used in this paper: mTOR, mammalian target of rapamycin; NALA, N-acetyl-leucine amide; 2DG, 2-deoxyglucose; AICAR, 5-aminoimidazole-4-carboxamide ribonucleoside; PCC, pigeon cytochrome c; AMPK, AMP-activated protein kinase.