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J Pharmacol Exp Ther. 2014 Nov;351(2):298-307. doi: 10.1124/jpet.114.218099. Epub 2014 Aug 14.

Anaplerotic metabolism of alloreactive T cells provides a metabolic approach to treat graft-versus-host disease.

Author information

1
Lycera Corporation, Ann Arbor, Michigan (G.D.G., C.L., B.S., X.L., L.-Y.H., C.T., A.H., A.W.O.); Departments of Chemical Biology (G.D.G., D.W.), Chemistry (G.D.G.), Pediatrics and Communicable Disease (J.L.M.F., V.T., C.A.B.), and Obstetrics and Gynecology (A.W.O.), University of Michigan, Ann Arbor, Michigan; Université Victor Segalen, Bordeaux, France (R.R.); Department of Medicine, Weill Cornell Medical College, New York, New York (C.A.L.); and SIDMAP, Los Angeles, California (L.B.).
2
Lycera Corporation, Ann Arbor, Michigan (G.D.G., C.L., B.S., X.L., L.-Y.H., C.T., A.H., A.W.O.); Departments of Chemical Biology (G.D.G., D.W.), Chemistry (G.D.G.), Pediatrics and Communicable Disease (J.L.M.F., V.T., C.A.B.), and Obstetrics and Gynecology (A.W.O.), University of Michigan, Ann Arbor, Michigan; Université Victor Segalen, Bordeaux, France (R.R.); Department of Medicine, Weill Cornell Medical College, New York, New York (C.A.L.); and SIDMAP, Los Angeles, California (L.B.) tony@lycera.com.

Abstract

T-cell activation requires increased ATP and biosynthesis to support proliferation and effector function. Most models of T-cell activation are based on in vitro culture systems and posit that aerobic glycolysis is employed to meet increased energetic and biosynthetic demands. By contrast, T cells activated in vivo by alloantigens in graft-versus-host disease (GVHD) increase mitochondrial oxygen consumption, fatty acid uptake, and oxidation, with small increases of glucose uptake and aerobic glycolysis. Here we show that these differences are not a consequence of alloactivation, because T cells activated in vitro either in a mixed lymphocyte reaction to the same alloantigens used in vivo or with agonistic anti-CD3/anti-CD28 antibodies increased aerobic glycolysis. Using targeted metabolic (13)C tracer fate associations, we elucidated the metabolic pathway(s) employed by alloreactive T cells in vivo that support this phenotype. We find that glutamine (Gln)-dependent tricarboxylic acid cycle anaplerosis is increased in alloreactive T cells and that Gln carbon contributes to ribose biosynthesis. Pharmacological modulation of oxidative phosphorylation rapidly reduces anaplerosis in alloreactive T cells and improves GVHD. On the basis of these data, we propose a model of T-cell metabolism that is relevant to activated lymphocytes in vivo, with implications for the discovery of new drugs for immune disorders.

PMID:
25125579
PMCID:
PMC4201277
DOI:
10.1124/jpet.114.218099
[Indexed for MEDLINE]
Free PMC Article

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