Anaplerotic Metabolism of Alloreactive T Cells Provides a Metabolic Approach To Treat Graft-Versus-Host Disease

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

来源：Journal of Pharmacology and Experimental Therapeutics, 2014, 351(2): 298-307.

DOI：10.1124/jpet.114.218099

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 C-13 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.

• 出版日期2014-11