PT  - JOURNAL ARTICLE
AU  - Gary D. Glick
AU  - Rodrigue Rossignol
AU  - Costas A. Lyssiotis
AU  - Daniel Wahl
AU  - Charles Lesch
AU  - Brian Sanchez
AU  - Xikui Liu
AU  - Ling-Yang Hao
AU  - Clarke Taylor
AU  - Alexander Hurd
AU  - James L. M. Ferrara
AU  - Victor Tkachev
AU  - Craig A. Byersdorfer
AU  - Laszlo Boros
AU  - Anthony W. Opipari
TI  - Anaplerotic Metabolism of Alloreactive T Cells Provides a Metabolic Approach To Treat Graft-Versus-Host Disease
AID  - 10.1124/jpet.114.218099
DP  - 2014 Nov 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 298--307
VI  - 351
IP  - 2
4099  - http://jpet.aspetjournals.org/content/351/2/298.short
4100  - http://jpet.aspetjournals.org/content/351/2/298.full
SO  - J Pharmacol Exp Ther2014 Nov 01; 351
AB  - 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 13C 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.