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

Gary D. Glick, Rodrigue Rossignol, Costas A. Lyssiotis, Daniel Wahl, Charles Lesch, Brian Sanchez, Xikui Liu, Ling Yang Hao, Clarke Taylor, Alexander Hurd, James L.M. Ferrara, Victor Tkachev, Craig A. Byersdorfer, Laszlo Boros, Anthony W. Opipari

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

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 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.

Original languageEnglish
Pages (from-to)298-307
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume351
Issue number2
DOIs
StatePublished - 1 Nov 2014
Externally publishedYes

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